Transcript Phase I GMP Requirements

Combination Products
Presented by: Karen S. Ginsbury
For: IFF
March 2014
PCI
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Purpose of the Seminar
•Review regulatory requirements:
• Medical device
• Drug
• Biologicals
• Human Cell and Tissue Therapy Products
• Combination Products
• Other?
•Quality System – What is appropriate
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Regulation of Drugs and Devices
QSR / cGMP Regulations
•LEGISLATION
•REGULATION
•GOOD MANUFACTURING PRACTICE
•CURRENT
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What is a Combination Product
•21 CFR Part 3
•MEDDEV
Let’s take a look
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MED DEV – Not legislation
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Combination products: medical
device, drug or both?
• Products that share the attributes
of two categories of products
• In each scenario below, would you
consider the combination product
a medical device, medicinal
product or equally both?
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Drug Product, Device or Both?
• Contact lens care product that is indicated to disinfect,
clean, rinse and hydrate contact lens
• Water to be used for injections, IV fluids and plasma
volume expanders
• Syringe needle applicator and insulin form a single integral
unit that is intended exclusively for use in the given
combination for one-time administration of insulin and is
not reusable
• Bone void filler to repair bone defects by which the
primary action is a physical means (matrix) to provide a
volume and scaffold for osteoconduction, where an
additional medicinal substance is incorporated to assist
and complement the action of the matrix by enhancing
the growth of bone cells
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Drug Product, Device or Both?
(In the EU – NOT in USA)
• Contact lens care product that is indicated to disinfect,
clean, rinse and hydrate contact lens – MD Accessory
• Water to be used for injections, IV fluids and plasma
volume expanders –
Drug Product
• Syringe needle applicator and insulin form a single integral
unit that is intended exclusively for use in the given
combination for one-time administration of insulin and is
not reusable –
Drug Product
• Bone void filler to repair bone defects by which the
primary action is a physical means (matrix) to provide a
volume and scaffold for osteoconduction, where an
additional medicinal substance is incorporated to assist
and complement the action of the matrix by enhancing
the growth of bone cells –
Medical Device
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In EU
•A combination product is regulated in
Europe by either the Medical Device
Directive MDD 93/42/EEC or the Medicinal
Product Directive 2001/83/EC
•A general rule is that the primary mode of
action (or function) of the product dictates
how it is regulated
•Therefore, a product never can be both a
medicinal product and possess CE Marking
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http://www.fda.gov/MedicalDevices/
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Device Advice
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What is a Combination Product
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The Rule
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Cross-labeled or
Co-Packaged and Single-entity
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Streamline
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Add to GMP Regs 21 CFR 211
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Add to QSR 21CFR Part 820
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Questions put to FDA
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More Questions
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Combination Products
• This guidance has been prepared by the Office of
Combination Products in the Office of the
Commissioner in cooperation with the Center for
Biologics Evaluation and Research (CBER), the
Center for Drug Evaluation and Research (CDER),
and the Center for Devices and Radiological Health
(CDRH) at the Food and Drug Administration.
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cGMP:
• For purposes of this guidance document, the term
current good manufacturing practice refers to the
current good manufacturing practice regulations for
drugs and most biological products under:
• 21 CFR Parts 210 and 211,
• 21 CFR Parts 600-680 for certain biological products
• 21 CFR Part 820: QSR for devices
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What is a combination product?
A product composed of any combination of:
•a drug and a device
• a biological product and a device
• a drug and a biological product
• a drug, device, and a biological product
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21CFR 3.2(e)
A combination product includes:
1.A product comprising two or more regulated components that are
physically, chemically, or otherwise combined or mixed and produced
as a single entity
2.Two or more separate products packaged together in a single
package or as a unit
3.A drug, device, or biological product packaged separately that
according to its investigational plan or proposed labeling is intended
for use only with an approved individually specified drug, device, or
biological product where both are required to achieve the intended
use
4.Any investigational drug, device, or biological product packaged
separately that according to its proposed labeling is for use only with
another individually specified investigational drug, device, or
biological product where both are required to achieve the intended
use, indication, or effect.
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CGMP – Section 501 Food Drug and
Cosmetics Act
•Section 501 authorizes FDA to
establish current good manufacturing
practice to avoid adulteration of drugs
•Adulteration includes a failure of the
drug, biological product, or device to
be manufactured in accordance with
current good manufacturing practice,
regardless of whether the product is
actually deficient in some respect.
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Purpose of GMP
•Current good manufacturing practice
regulatory provisions are intended to
ensure that the drug, biological
product, or device is not adulterated
so as:
•to ensure the product possesses adequate
strength, quality, identity, and purity of a
drug or biological product
•to ensure compliance with performance
standards for a device.
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21 cfr Part 820: QSR
A: General
B: Quality System Requirements
C: Design Controls
D: Document Controls
E: Purchasing Controls
F: Identification & Traceability
G: Production and Process Controls
H: Acceptance Activities
I: Non Conforming Product
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J: CAPA
K: Labeling and Packaging
Controls
L: Handling, Storage,
Distribution & Installation
M: Records
N: Servicing
O: Statistical Techniques
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21 cfr part 211:
GMP for Finished Pharmaceuticals
A. General
B. Organization &
Personnel
C. Facilities
D. Equipment
E. Component Controls
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F.
G.
H.
I.
J.
K.
Production Controls
Packaging Controls
Warehousing
Laboratory Controls
Documentation
Returns and Recalls
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CGMP vs QSR
Combination Drugs Guideline
• Considerable overlap in the CGMP and QS
regulations
• Both establish requirements for management,
organization, and personnel
• Both require documentation and record keeping
• Both allow flexibility for manufacture
• FDA considers the CGMP and the QS regulations to
be similar: they are meant to achieve the same
goals
• Prior to combining product follow QSR or cGMP
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Risk Management
•What could go wrong:
•With the drug
•With the device
•With the biological
•With the combination
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Quality Management
•Requires management involvement
and commitment: resources
•For investigational drugs may have
same individual performing Quality
functions who is performing
production or other functions. In this
case, also have independent review
•Always involves SOPs, documentation
and control of activities
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Personnel Training
• All personnel should have the education,
experience and training or any combination thereof
to enable that person to perform the assigned
function
• In particular, personnel should have the appropriate
experience to prepare the investigational product
and be familiar with QC principles and acceptable
methods for complying with the statutory
requirement of CGMP
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Facilities and Equipment
• Sufficient space, clean environment, appropriate
construction
• Appropriate lighting, ventilation, and heating
• Appropriate cooling, plumbing, washing, and sanitation
• Appropriate air handling systems (e.g., laminar flow hoods)
to aid in preventing contamination and cross-contamination
of product
• Appropriate equipment that will not contaminate the
product; not be reactive, additive, or absorptive with
product; is properly maintained, calibrated, cleaned, and
sanitized at appropriate intervals following written
procedures
• Prevent contamination and cross-contamination
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Purchasing Controls
• Written procedures describing:
handling, review, and acceptance and control of
components used in the production of an
investigational product
• Components should be e.g. segregated, labeled,
until examined or tested, as appropriate, and
released for use in production
• Handle and store to prevent degradation or
contamination
• Keep records of receipt and use
• Acceptance criteria, COAs and identity testing
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QC Controls
• Test methods scientifically sound…
• Validation? Stability indicating?
• OOS results: MUST have a written procedure and
follow it
• Written, approved specifications
• Calibrated, qualified lab equipment
• Sample log-in
• Record keeping
• Standards….must be valid
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Documentation
•Production records
•Laboratory records
•Deviation reporting
•Change: control and audit trails
•Batch release records
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Packaging Controls
•May be particularly complex for
clinical trials because of placebo
•Make sure no previous product
•Avoid mix-ups
•Document line clearance
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Statistical Controls
•Use of valid statistical methods
•Define in written procedures
•DO NOT select the method AFTER
you have the data
•May need assistance of statisticians
beyond those within the company
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Validation
•Confirmation by examination and
provision of objective evidence that
the particular requirements for a
specific intended use can be
consistently fulfilled
21cfr 820.3 (Definitions)
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Validation
•Validation: Providing documented
evidence, in accordance with a preapproved protocol that a system,
equipment, process, analytical method
does what it is designed to do
repeatedly and reliably. Have predetermined acceptance criteria /
specification
CDER / EU for drugs
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Process Validation
Establishing by objective evidence
that a process consistently produces a
result or product meeting its
predetermined specifications
21cfr 820.3 (Definitions)
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Design Validation
Establishing by objective evidence
that device specifications conform
with user needs and intended use(s).
21cfr 820.3 (Definitions)
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Verification
•Confirmation by examination and
provision of objective evidence that
specified requirements have been
fulfilled
21cfr 820.3 (Definitions)
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Subpart C - Design Controls - 2
820.30 (g): Design Validation:
•Establish and maintain procedures for
validating the device design.
•Performed under defined operating
conditions on initial production units,
lots or batches.
•Ensure that devices conform to defined
user needs and intended uses
•include testing of production units under
actual or simulated conditions of use
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Subpart C - Design Controls - 3
820.30 (g): Design Validation cont/:
•Include software validation and risk
analysis, where appropriate
•Results including identification of the
design, methods, date and individuals
performing the validation
documented in the DHF
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21 cfr 820.75
Process Validation
•Where the results of a process cannot
be fully verified by subsequent
inspection and test, the process shall
be validated with a high degree of
assurance and approved according to
established procedures
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21 cfr 820.75
Process Validation
•A man who makes a mistake and does not
correct it is making another mistake
(Confucius)
•When changes or process deviations occur,
the manufacturer shall review and evaluate
the process and perform revalidation
where appropriate.
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Change Control
•Remember Remedia:
“It wasn’t a change it was an
improvement!”
•All changes are initiated as
improvements
•All changes have the potential to
“in”validate a valid process
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21 cfr 820.70 (b)
•Production and process changes:
•Establish and maintain procedures for
changes to a specification, mehtod,
process or procedure
•Changes should be verified or where
appropriate validated before
implementation and these activities
documented.
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Thank You
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