Transcript Drug/Device Combination Products

2Exceed
Regulatory requirements for
- Drug/Device Combination Products
- Medical Devices
- Cosmetics
14 April 2016
Ingrid K. Malmberg
Purpose and program
Purpose: Give a short introduction to the legislation in EU and USA to understand the mindset between
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Drug/Device Combination Products (DDCP)
Medical Devices
Cosmetics
continued by a deeper understanding of the requirements for Quality Management Systems.
Program:
15:30 Welcome and introduction
15:35 Regulatory requirements Drug/Device Combination Products (DDCP), Medical Devices and
Cosmetics
16:30 Short break
16:40 Regulatory requirements for Quality Management Systems for Drug/Device Combination
Products (DDCP), Medical Devices (MD) and Cosmetics
17:30 Sandwich
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Who am I?
Ingrid K. Malmberg, Cand. Pharm.
2012 -
2Exceed, Partner and QA/RA Consultant
2010 – 2011 Haldor Topsøe, General Manager, Quality
2004 – 2010 Coloplast, VP for Corp. Quality and Environmental Affairs
1998 – 2003 Coloplast, Director, Global Quality and Regulatory Affairs
1990 – 1997 Coloplast, Quality Manager of the Ostomy Division
1983 – 1990 Ferrosan A/S, Production Manager for Finished Pharmaceuticals
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2Exceed
Mindset and regulatory requirements for
- Drug/Device Combination Products (DDCP),
- Medical Devices
- Cosmetics
What is a combination product?
21CFR, Part 3 – Product Jurisdiction, §3.2 Definitions.
A product comprised of two or more regulated components, i.e.,
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drug/device
biologic/device
drug/biologic
drug/device/biologic
that are physically, chemically, or otherwise combined or mixed and produced as a single
entity. Single entity combination product.
Two or more separate products packaged together in a single package or as a unit and
comprised of drug and device products, device and biological products, or biological and
drug products. Co-packaged combination product.
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Primary mode of action
21CFR, Part 3 – Product Jurisdiction, §3.2 Definitions.
(m) Primary mode of action is the single mode of action of a combination product
that provides the most important therapeutic action of the combination product. The
most therapeutic action is the mode of action expected to make the greatest
contribution to the overall intended therapeutic effects of the combination product.
(k) Mode of action is the means by which a product achieves an intended therapeutic
effect or action. For purposes of this definition, ”therapeutic” action or effect includes
any effect or action of the combination product intended to diagnose, cure, mitigate,
treat, or prevent disease, or affect the structure of any function of the body.
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EU Directives and Regulation
Pharma
Medicinal
Products
Directive
(2001/83/EC)
Advanced
Therapy
Medicinal
Products
Regulation
(1394/2007)
Medical
Devices
Active
Implantable
Medical
Devices
Directive
(90/385/EEC)
IVD
In Vitro
Diagnostic
Medical
Devices
Directive
(98/79/EC)
Cosmetics
Regulation
(EC) No
1223/2009 on
Cosmetic
Products
(effective
July 2013)
Medical
Devices
Directive
(93/42/EEC)
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Definition of Medicinal Product
Medicinal product:
Any substance or combination of substances presented for treating or preventing
disease in human beings.
Any substance or combination of substances which may be administered to human
beings with a view to making a medical diagnosis or to restoring, correcting or
modifying physiological functions in human beings is likewise considered a medicinal
product.
Source: DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the
Community code relating to medicinal products for human use
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Definition of Medical device
Medical device means any instrument, apparatus, appliance, material or other article,
whether used alone or in combination, including the software necessary for its proper
application intended by the manufacturer to be used for human beings for the purpose of:
- diagnosis, prevention, monitoring, treatment or alleviation of disease,
- diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
- investigation, replacement or modification of the anatomy or of a physiological process,
- control of conception,
and which does not achieve its principal intended action in or on the human body by
pharmacological, immunological or metabolic means, but which may be assisted in its
function by such means;
Source: Council Directive 93/42/EEC concerning Medical Devices
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Definition of Cosmetics
Cosmetic products are substances or mixtures of substances intended to be placed
in contact with the external parts of the human body (epidermis, hair system, nails,
etc.) or with the teeth and the mucous membranes of the oral cavity with a view
exclusively or mainly to cleaning them, perfuming them, changing their appearance,
protecting them, keeping them in good condition or correcting body odours.
Source: Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic
Products.
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Combination Products in Europe
No designated regulation for Combination Products in Europe and no designated
agency, but….
Medical devices incorporating, as an integral part, an ancillary medicinal
substance: Medical devices may be assisted in their function by pharmacological,
immunological and metabolic means but with primary mode of action as mechanical
The quality, safety and usefulness of the substance must be verified by analogy with
the methods specified in Annex I to Directive 2001/83/EC
Drug-delivery products regulated as medicinal products or medical devices:
This category involves a device that is intended to administer a medicinal product.
The safety and intended use of the device must be verified by analogy with methods
specified in Annex I (Essential Requirements) to Directive 93/42/EEC
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Essential Requirements (Annex I), check list, example
II. REQUIREMENTS REGARDING DESIGN AND
CONSTRUCTION
Applic
ability
Compliance
document
Reference
standard
Yes
Report ID
ISO 10993-X:2009
7. Chemical, physical and biological properties
7.1 The device must be designed and manufactured in such a way as to guarantee
the characteristics end performance referred to in section I on the ‘General
Requirements’. Particular attention must be paid to:
- the choice of materials used, particularly as regards toxicity and where
appropriate, flammability,
- The compatibility between the materials used and biological tissues, cells and
body fluids, taking account of the intended purpose of the device,
- Where appropriate, the results of biophysical or modelling research whose
validity has been demonstrated beforehand.
7.2 The device must be designed, manufactured and packed in such a way as to
minimize the risk posed by contaminants and residues to the persons involved in the
transport, storage and use of the devices and to the patients, taking account of the
intended purpose of the product. Particular attention must be paid to the tissues
exposed and to the duration and frequency of exposure.
7.3 The device must be designed and manufactured in such a way that they can be
used safely with the materials, substances and gases with which they enter into
contact during their normal use or during routine procedures; if the devices are
intended to administer medicinal products they must be designed and manufactured
in such a way as to be compatible with the medicinal products concerned according
to the provisions and restrictions governing these products and that their
performance is maintained in accordance with the intended use.
7.4 Where a device incorporates as an integral part, a substance which, if used
separately, may be considered to be a medicinal product as defined in Article 1 of
Directive 2001/83/EC…..
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CE-marking
Followed by the identification
number of Notified Body
(class I medical devices exempt)
Manufacturer: Company name and address of legal manufacturer
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Procedure packs/ co-packaged combination products.
Article 12 in the Medical Device Directive
CE
CE
CE
1234
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CE
The individual medical devices are used within the intended purpose identified by the
original manufacturer
Transfer of original manufacturer and CE-mark to the package labelling
Expiry date (shortest dated component) and lot number for traceability
Manufacturer shall provide IFU for the individual medical devices in accordance with the
original manufacturer’s labelling, including any warnings, precautions etc.
Manufacturer shall draw up a declaration, by which he states verified mutual compatibility,
transferred relevant information and instructions and subject to relevant control activities.
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Procedure packs/ co-packaged combination products.
Article 12 in the Medical Device Directive
CE
CE
Not
CEmarked
CE
CE-marking if the Device is Primary Mode of Action
Device
Drug
Device
Drug
Pharma if the drug product is the Primary Mode of Action
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References
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Draft NB-MED/ 2.9 REC 2 – Combination of CE-marked and non-CE-marked
medical devices and non-medical devices
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MHRA – guidance on legislation – Borderlines with Medical Devices, June 2013
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IMB – Guide for manufacturers of systems and procedure packs regarding
legislative requirements, SUR-G0015-2, 9 AUGUST 2010
Medical Device Directive 93/42/EEC
MEDDEV 2.1/3 rev. 3 Borderline products, drug-delivery products and medical
devices incorporating, as an integral part, an ancillary medicinal substance or an
ancillary human blood derivative
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2Exceed
Short break
2Exceed
Regulatory Requirements for Quality
Management Systems for
- Drug/device combination products,
- Medical Devices and
- Cosmetics
21CFR, Code of Federal Regulation
21 CFR, Part 210 – Current Good Manufacturing Practice in Manufacturing,
Processing, Packing, or Holding of drugs; general
21CFR, Part 211 – Current Good Manufacturing Practice for Finished
Pharmaceuticals
21CFR, Part 820 – Quality System Regulation for Medical Devices
21CFR, Part 4 – Regulation of Combination Products
US Pharmacopeia (USP) monographs
for Drug products and materials
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21CFR, Part 4: cGMP for co-packed products and
single-entity combination products
If the operating manufacturing control system is Part
820 (Quality System Regulation) compliant
Additional CGMP
requirements
Title
If the operating manufacturing control system is Part
210/211 (cGMP regulation) compliant
Additional QS
requirements
Title
§211.84
Testing and approval or rejection of
components, drug product
containers, and closures
§820.20
Management responsibility
§211.103
Calculation of yield
§820.30
Design controls
§211.132
Tamper-evident packaging
requirements for over-the counter
(OTC) human drug products
§820.50
Purchasing controls
§211.137
Expiration dating
§820.100
Corrective and preventive action
§211.165
Testing and release for distribution
§820.170
Installation
§211.166
Stability testing
§820.200
Servicing
§211.167
Special testing requirements
§211.170
Reserve samples
Including all subsections, as appropriate
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EU regulation for medicinal products
and for medical devices
Medicinal Products Directive 2001/83/EC (MPD) as amended
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Eudralex - Volume 4, Good manufacturing practice (GMP)
Guidelines http://ec.europa.eu/health/documents/eudralex/vol-4/
Ph. Eur monographs for products and materials
Medical Devices Directive 93/42/EEC (MDD) as amended
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MEDDEV guidelines http://ec.europa.eu/health/medical-devices/documents/guidelines/
Harmonized horizontal standards and product standards (vertical)
http://ec.europa.eu/enterprise/policies/european-standards/harmonisedstandards/medical-devices/index_en.htm
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MEDDEV Guidelines
Most important
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MEDDEV 2.4/1 rev.9 Classification of medical devices
MEDDEV 2.1/3 rev. 3 Borderline products, drug-delivery products and medical
devices incorporating, as an integral part, an ancillary medicinal substance or an
ancillary human blood derivative
MEDDEV 2.7/1 rev.3 Clinical evaluation: Guide for manufacturers and notified
bodies
MEDDEV 2.7/4 Clinical investigations: A guide for manufacturers and notified
bodies
MEDDEV 2.12/1 rev. 8 Medical devices vigilance system
MEDDEV 2.12/2 rev.2 Post Market Clinical Follow-up studies
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Harmonized horizontal standards
Most important:
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ISO 13485 Medical Devices - Quality management systems – Requirement for
regulatory purposes
ISO 14155 Clinical investigation of medical devices for human subjects
ISO 11135-38 Sterilization of health care products
ISO 11607 Packaging for terminally sterilized medical devices
ISO 14971 Application of risk management to medical devices
IEC 62366 Application of Usability Engineering to Medical Devices (Human Factor)
ISO 10993 Biological evaluation of medical devices
ISO 15223-1 – Medical devices - Symbols to be used with medical device labels,
labeling and information to be supplied - Part 1: General requirements
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Vertical harmonized product standards
Examples:
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ISO 11608 - Pen-injectors for medical use
EN 455 - Medical gloves for single use
EN 1618 – Catheters other than intravascular catheters – test methods for
common properties
EN 10555 - Sterile, single-use intravascular catheters
ISO 15747 - Plastic containers for intravenous injections
ISO 594 - Conical fittings with a 6 % (Luer) taper for syringes, needles and certain
other medical equipment
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Pharmaceutical Quality System - Q10
© ICH, November 2010
ISO 22716 Cosmetics – Good Manufacturing Practices
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Scope
Terms and definitions
Personnel
Premises
Equipment
Raw materials and packaging
materials
Production
Finished products
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Quality control laboratory
Products out of specification
Wastes
Subcontracting
Deviations
Complaints and recalls
Change control
Internal audit
Documentation
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ISO 13485:2016
Process-based Quality Management System
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ISO 13485: 2016, Product Realization
Business processes
Customer
related
processes
Customer
Design and
Development
Purchasing
Manufacturing
Final inspection
Further orders
Despatch
Happy customer
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Governance
Product
category
Regulatory requirements
QMS
requirements
Responsible
authority
Drug
products
EU Directive 2001/83/EC
for Medicinal products for
human use
GMP regulation,
Eudralex, vol. 4
Lægemiddelstyrelsen
Medical
devices
EU Directive 93/42/EEC for ISO 13485
Medical Devices
Notified Body
Cosmetics
EU Regulation 1223/2009
for Cosmetic Products
Miljø-styrelsen
ISO 22716
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21CFR, Part 4: cGMP for co-packed products and
single-entity combination products
If the operating manufacturing control system is Part
820 (Quality System Regulation) compliant
Additional CGMP
requirements
Title
If the operating manufacturing control system is Part
210/211 (cGMP regulation) compliant
Additional QS
requirements
Title
§211.84
Testing and approval or rejection of
components, drug product
containers, and closures
§820.20
Management responsibility
§211.103
Calculation of yield
§820.30
Design controls
§211.132
Tamper-evident packaging
requirements for over-the counter
(OTC) human drug products
§820.50
Purchasing controls
§211.137
Expiration dating
§820.100
Corrective and preventive action
§211.165
Testing and release for distribution
§820.170
Installation
§211.166
Stability testing
§820.200
Servicing
§211.167
Special testing requirements
§211.170
Reserve samples
Including all subsections, as appropriate
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cGMP for Combination Products – Draft Guidance
Office of Combination Products
http://www.fda.gov/downloads/Regulatory
Information/Guidances/UCM429304.pdf
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21CFR, Part 4: cGMP for co-packed products and
single-entity combination products
If the operating manufacturing control system is Part
820 (Quality System Regulation) compliant
Additional CGMP
requirements
Title
If the operating manufacturing control system is Part
210/211 (cGMP regulation) compliant
Additional QS
requirements
Title
§211.84
Testing and approval or rejection of
components, drug product
containers, and closures
§820.20
Management responsibility
§211.103
Calculation of yield
§820.30
Design controls
§211.132
Tamper-evident packaging
requirements for over-the counter
(OTC) human drug products
§820.50
Purchasing controls
§211.137
Expiration dating
§820.100
Corrective and preventive action
§211.165
Testing and release for distribution
§820.170
Installation
§211.166
Stability testing
§820.200
Servicing
§211.167
Special testing requirements
§211.170
Reserve samples
Including all subsections, as appropriate
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§ 820.30 Design Controls
General.
Each manufacturer of any class III or class II device, and the class I devices listed below shall
establish and maintain procedures to control the design of the device in order to ensure that
specified design requirements are met.
The following class I devices are subject to design controls:
Devices automated with computer software; and the devices listed in the following chart:
Section
Device
868.6810
Catheter, Tracheobronchial Suction
878.4460
Glove, Surgeon’s
880.6760
Restraint, Protective
892.5650
System, Applicator, Radionuclide,
Manual
892.5740
Source, Radionuclide Teletherapy
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Design control process in the Waterfall model
• Design and
Design and Development Planning
development planning
• Design input
• Design verification
User
needs
Design
review
Design
input
• Design validation
• Design review
Design
process
• Design output
Design
verification
• Design transfer
• Risk assessment
• Design History File
Design
output
Design
validation
Medical
device
Risk Assessment
• Device Master Record
• Design Changes
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Design and Development Planning
The organization shall establish and
maintain plans that describes the design
and development activities and define
responsibilities for implementation.
The purpose of planning is to ensure
the design process is appropriately
controlled and the product quality
objectives are met.
During the planning the organization
shall determine
• the design and development stages,
• the review, verification, validation and
design transfer activities that are
appropriate at each stage and
• the responsibilities an authorities for
design and development
The organization shall manage the
interfaces between different groups
involved in design and development to
ensure effective communication and
assignment of responsibilities.
Design and Development Planning
User
needs
Design
review
Design
input
Design
process
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
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User needs and Design input
Design input requirements shall be
determined and records maintained.
These inputs shall include
• functional, performance and
safety requirements,
• applicable statutory and
regulatory requirements,
• where applicable, information
derived from previous similar
designs,
• other requirements essential for
design and development, and
• output of risk management.
These inputs shall be reviewed for
adequacy and approved.
Requirements shall be complete,
unambiguous and not in conflict
with each other.
Design and Development Planning
User
needs
Design
review
Design
input
Design
process
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
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Design and Development
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Design Verification – “did we design it right?”
Verification shall be performed
in accordance with planned
arrangements to ensure that
the design and development
outputs have met the design
input requirements. Records of
the results of the verification
and any necessary actions
shall be maintained.
Design and Development Planning
User
needs
Design
input
Design
process
Verification activities requiring
testing shall be performed in
accordance with written
protocols/test methods.
Design verification shall be
based on products
manufactured under defined
process validated operating
conditions or their equivalents.
Design
review
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
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Design validation – “did we design the right device?”
Design validation shall be performed
in accordance with design and
development plan to ensure that the
resulting product conform to defined
user needs and intended uses.
Records of the results of validation
and any necessary actions shall be
maintained.
As part of design validation, the
organization shall perform clinical
evaluations and/or evaluation of
performance of the medical device,
as required by national or regional
regulations.
Design validation shall include
software validation
Design and Development Planning
User
needs
Design
review
Design
input
Design
process
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
Design validation shall be performed
under defined operating conditions
on initial production batches or their
equivalents.
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Design Review – “are we on track?”
At suitable stages, systematic
reviews of design and development
shall be performed in accordance with
planned arrangements
• to evaluate the ability of the results
of design and development to meet
requirements, and
• to identify any problems and
propose necessary actions.
Participation in such reviews shall
include representatives of functions
concerned with the design and
development stages being reviewed,
as well as other specialist personnel.
Records of the results of the reviews
and any necessary actions shall be
maintained.
Design and Development Planning
User
needs
Design
review
Design
input
Design
process
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
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Product Risk Assessment and
Usability Engineering (Human Factor)
The organization shall establish
documented requirements for risk
management throughout product
realization. Records arising from risk
management shall be maintained.
(ISO 14971)
Design and Development Planning
User
needs
Design
input
Usability: Characteristic of the user
interface that establishes
effectiveness, efficiency, ease of user
learning and user satisfaction
(ISO/IEC 62366)
Human factors: “…the application of
knowledge about human capabilities
(physical, sensory, emotional and
intellectual) and limitations to the
design and development of tools,
devices, systems, environments and
organizations…” (ANSI/AAMI HE75)
Design
review
Design
process
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
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ISO 14971 – Medical
devices – Application of
risk management to
medical devices
Figure 1 - A schematic
representation of the risk
management process
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Design transfer
Design History File (DHF) contains or
reference the records necessary to
demonstrate that the product was
developed in accordance with the
approved plan.
Design and Development Planning
User
needs
Design
input
Device Master Record (DMR) is the
”translation” of the design into
production instructions and
specifications for a finished product
with respect to purchasing,
production and inspection.
During design transfer it shall be
ensured that critical product risks are
correctly transferred into labeling or
process risk assessment.
The output from process risk
assessment is transferred to the
Validation Master Plan and the quality
control specifications.
Design
review
Design
process
Design
verification
Design
output
Design
validation
Medical
device
Risk Assessment
DHF+DMR
completed
Design
transfer
Change
Control
Technical file, CEmarking and market
clearance in ROW
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2Exceed
Thank you!
Questions:
Ingrid K. Malmberg
42 74 09 30
[email protected]
Likørstræde 2
2800 Kgs. Lyngby