Transcript Working Group on GMP/Supplier QC Presented by Barbara Falco

IPAC-RS GMP Guideline for OINDP
Component Suppliers:
Development, Application, and Use
Barbara Falco (KOS), Chair of IPAC-RS Supplier Quality Control
Working Group
Outline
 Background
 Process for Development of the IPAC-RS
GMP Guideline
 Content, Application, and Use of the
Guideline
 FAQs
 Next Steps and Conclusion
Background:
Why IPAC-RS?
Definitions and Acronyms
 IPAC-RS – International Pharmaceutical Aerosol
Consortium for Regulation and Science
 OINDP – Orally Inhaled and Nasal Drug Products
(e.g., MDIs, DPIs, Nasal Sprays, etc)
 OINDP manufacturer: Pharmaceutical company
that manufactures and sells OINDP
 N-1 Supplier (aka OINDP component supplier):
Supplier of components or materials directly to the
OINDP manufacturer
 N-2 Supplier: Supplier of materials to n-1 supplier
IPAC-RS
• 1989: International Pharmaceutical Aerosol Consortium
(IPAC) formed to address regulatory consequences for
MDIs of Montreal and Kyoto Protocols
• 1999: IPAC formed a Working Group to prepare comments
on the FDA draft CMC Guidances for MDIs and DPIs
• 2001: International Pharmaceutical Aerosol Consortium for
Regulation and Science (IPAC-RS) formed as a separate
Consortium
– IPAC-RS Mission: To advance consensus-based and
scientifically driven standards and regulations for inhaled and
nasal drug products (OINDP)
– IPAC-RS Overall Goal: Development of scientifically justified
regulatory approaches for orally inhaled and nasal drug
products
IPAC-RS Member Companies
Aradigm
AstraZeneca
Boehringer Ingelheim
Eli Lilly
GlaxoSmithKline
INyX
Kos
Nektar Therapeutics
Novartis
Novo Nordisk
Pfizer
Sanofi-Aventis
Schering-Plough
Why Supplier QC?
OINDP Components
Sources of Images:
IPAC-RS SQC WG and suppliers’ public catalogues
FDA-Required CMC Tests for OINDP
Component quality plays a critical role in many CMC tests
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Assessment of Packaging Materials
Appearance / Description of Product
Color
Identification (2 specific tests)
Chiral Specificity, if applicable
Microbial Limits
Microbial Challenge
Water Content
Alcohol Assay if applicable
Content Assay
Assay for other excipients
Net Content Weight
Leak Rate
Pressure Testing
Spray Pattern
Plume Geometry
Valve Delivery (Shot Weight)
Dose Content Uniformity (uniformity
of API delivered from mouthpiece)
Dose Content Uniformity Through
Canister Life (API delivered from
mouthpiece at beginning, middle,
and end of canister)
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Particle Size Distribution of API – Mass
Balance and Groupings (Cascade
Impactor)
Effect of Storage on Particle Size
Distribution
Microscopic Evaluation (particle size,
morphology, crystallinity, amorphous
forms, agglomerates, etc.)
Foreign particles (enumeration,
characterization)
Leachables
Extractables
Dissolved metals
Impurities and Degradation Products
Number of Doses Delivered
Effect of Resting Time
Priming and Re-priming
Drug Deposition on Mouthpiece and/or
Other Accessories
Profiling of Actuations Near Canister
Exhaustion
In vitro Dose Proportionality (multistrength doses)
Effect of Flow Rates
Impetus for Supplier QC Working Group
• IPAC-RS recognized that:
– Quality of OINDP components is critical to quality of
drug/device combination and significantly impacts many
required CMC tests
– Some aspects of quality control are particularly important
to OINDP components, e.g.,
• Change Control
• Control of Extractables
– No existing quality guideline provides guidance specific
to development and manufacture of OINDP components
• Quality practices vary widely between component suppliers
• OINDP manufacturers (IPAC-RS members) each have slightly
different expectations for component suppliers, and audit them
using different standards.
Formation of Supplier QC Working Group
• IPAC-RS formed the Supplier QC Working Group, made up
of representatives from OINDP manufacturers and
suppliers
– Leachables and Extractables was spun off as a separate topic
within the Product Quality Research Institute (PQRI)
– PQRI L&E Working Group has issued specific recommendations
regarding extractables and leachables control, testing, and
thresholds
• Supplier QC Working Group Mission:
– To encourage quality through design rather than through testing and
enable the provision of consistently high quality OINDP components
by promoting the implementation of robust quality systems at
OINDP component manufacturers
– To simplify the quality control process by promoting harmonized
quality standards for OINDP components
Working Group Objectives
• Survey Component Suppliers and OINDP Manufacturers to
determine:
– Whether a quality guideline for OINDP suppliers is needed
– If so, what topics this guideline should address
• Develop guideline for OINDP component suppliers
• Conduct education/training for OINDP manufacturers and
their suppliers on use of the GMP Guideline
• Consider development of an auditing service or certification
of suppliers against the GMP Guideline
Development of the IPAC-RS
GMP Guideline
Supplier Survey
• Survey of OINDP n-1 suppliers completed in
2001/2002
• Suppliers surveyed specialize in:
– Pumps and valves
– Molded rubber components
– Printed materials
– Specialty chemicals
– Plastic components
– Etc
• 14 suppliers responded
• Also surveyed OINDP manufacturers regarding
expectations for OINDP Suppliers
Conclusions from Survey
• Survey results showed differences in quality expectations
among OINDP manufacturers and differences in quality
practices among OINDP suppliers.
• Need for quality guidance for OINDP suppliers
• Review of existing quality guidelines (ISO, PS 9000)
showed insufficient guidance on topics important to
OINDP
• Based on survey results and review of quality guidelines,
Supplier QC Working Group defined areas where further
guidance specific to OINDP components is needed.
– These areas became the topics addressed by the
IPAC-RS GMP Guideline
Topics Addressed by IPAC-RS Guideline
 TESTING AND RELEASE
– Characterization and functionality testing of OINDP
components
– Control of ancillary materials and extractables
– Components and materials use-by/expiry date and shelf-life
determination
 QUALITY SYSTEMS
– Supply agreements, specifications, quality agreements, and
documentation
– Design and development planning
– Subcontracting, supplier qualification, and supplier data
verification
– Change control and notification
– Quality unit authority and responsibilities
– Product recalls and complaints
– Drug master files (DMFs)
Topics Addressed by IPAC-RS Guideline
 ENVIRONMENT/CLEANING
– Environment
– Equipment use and cleaning; dedicated/non-dedicated
equipment; cleaning validation
– Component cleaning
– Foreign particulates
Development of the IPAC-RS Guideline
 Working Group drafted text addressing each topic
– Reviewed text to ensure harmonization with and no
duplication of existing quality guidelines
 Based on supplier suggestion, Working Group
decided to incorporate IPAC-RS Guideline into PS
9000 Guideline for Pharmaceutical Packaging
Materials
– PS 9000 already used by many OINDP component
suppliers
– Includes ISO 9001:2000 and ISO 9004:2000
– Obtained permission from ANSI and PQG/IQA for use
of PS 9000 and ISO text
Guideline Review Process
• Consensus Process:
– Draft Guideline discussed, reviewed, and approved by Working
Group members
– Draft Guideline circulated to IPAC-RS Board of Directors for
review, comment, and approval (13 OINDP manufacturers)
– Draft Guideline circulated to external reviewers for comment
• External reviewers included most major n-1 OINDP suppliers (3M,
Bespak, Honeywell, Kinetics, Pfeiffer, Presspart, Valois, West), and
individuals at the PQG
• Comments received from 8 of 9 external reviewers
• Overall, comments were very positive and indicated that the
Guideline will be useful
• Comments were reviewed by the Working Group, and revisions
were made to the Guideline. Where revisions were not appropriate,
IPAC-RS responded to the commenter indicating why the revision
was not made
Guideline Review Process
• Regulatory Review:
– IPAC-RS also sought feedback on Guideline from FDA
• Feedback was positive and noted that Guideline is in
alignment with FDA’s new Quality by Design Initiative
• FDA has not provided formal approval/endorsement because
the Guideline did not go through an official FDA review
process
– IPAC-RS welcomes comments from other regulatory
authorities
– NOTE: OINDP Suppliers are not regulated by FDA or
other regulatory authorities. The IPAC-RS Guideline
does not change this status
Application and Use of the
IPAC-RS GMP Guideline
Application
 Applies to suppliers of components for OINDP not
regulated by FDA or other device regulations, e.g.,
– Canister or reservoir
– Actuator
– Pump
– etc
 Does not address devices or device
manufacturers
 Applies to n-1 suppliers
– n-2 and n-3 suppliers who supply to n-1 suppliers are
encouraged to read and follow Guideline
Layout
 Guideline includes requirements from 3 standards:
– ISO 9001 (Boxed black text)
– PS 9000 (Boxed blue text)
– IPAC-RS (Boxed green text)
 Guideline also includes ISO 9004 as guidance
(non-boxed black text)
 Layout follows layout of PS 9000, e.g.,
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ISO 9004 1
ISO 9001 1, 1.1, 1.2
PS 9000 1, 1.1,1.2
IPAC-RS 1, 1.1, 1.2
ISO 9004 2
ISO 9001 2, etc.
Use
 N-1 suppliers are expected to read and follow the
contents of the IPAC-RS, PS 9000, and ISO 9001
sections of the Guideline (boxed text)
– ISO 9004 text provides additional guidance but is not required
 N-1 suppliers may be audited by their customers
against IPAC-RS, PS 9000, and ISO 9001 sections
 Guideline allows room for variation based on needs of
customer and supplier:
– Many requirements are "as defined by the customer," "as agreed
between the supplier and the customer," or "where applicable“
 Communication between the supplier and customer is
emphasized in the Guideline and is a key element of the
Guideline
Use: Informational Sections
 IPAC-RS Sections of the Guideline includes several
informational sections
– Drug Master Files (DMF)
– Process Analytical Technology (PAT)
 These sections are included for information only and
are not required
– For example, DMF section explains what a DMF is, its
uses and benefits, and how an interested supplier may
obtain more information on DMFs. Suppliers are not
required to submit a DMF.
IPAC-RS GMP Guideline:
FAQs
IPAC-RS Guideline FAQs
Q: Why did IPAC-RS choose to incorporate its
Guideline into the PS 9000?
A: Suppliers on the Working Group noted that the PS
9000 standard is already used by many suppliers,
and that it includes ISO 9001, providing a useful
“all-in-one” standard addressing many areas of
GMP.
WG members agreed that it would be useful to
incorporate the IPAC-RS Guideline into the PS
9000, thus providing suppliers with a
comprehensive GMP Guideline.
IPAC-RS Guideline FAQs
Q: The format of the Guideline is confusing.
How do I know which sections to follow and
what is required?
A: All BOXED text (black, blue, and green) is
required, except for the IPAC-RS
informational sections on DMFs and PAT.
These sections are clearly marked “For
information only”. Non-boxed text is NOT
required.
IPAC-RS Guideline FAQs
Q: Who enforces the Guideline’s requirements?
A: Initially, your customers (OINDP manufacturers). It is
expected that most OINDP manufacturers will begin
auditing their suppliers against this Guideline.
IPAC-RS is also exploring the possibility of implementing
a certification process, whereby suppliers could be
certified against this guideline, or an independent
auditing service (similar to IPEA) that would audit against
the Guideline.
IPAC-RS Guideline FAQs
Q: I am an n-2 supplier (e.g., a resin manufacturer). Should
I still follow the Guideline?
A: We encourage you to read the Guideline, familiarize
yourself with its requirements, and implement its
requirements to the extent possible. However, n-2/n-3
suppliers are not required to follow the Guideline.
IPAC-RS Guideline FAQs
Q: If my customers don’t use the IPAC-RS Guideline,
should I still follow its requirements?
A: We encourage you to adhere to the Guideline’s
requirements if you are an OINDP supplier. Many
OINDP manufacturers will begin auditing against this
Guideline, and you may find that potential customers
expect/request that you follow the IPAC-RS Guideline.
In addition, the Guideline provides clarity as to the GMP
expectations for OINDP component suppliers, and may
therefore be useful to you in designing/improving your
processes.
IPAC-RS Guideline FAQs
Q: Some of the component properties listed in section
7.3.1.1 , Design and Development Planning, don’t apply
to components produced by my company. What do I do?
A: Notice that the list of component properties in Section
7.3.1.1 is prefaced by:
“…the following relevant properties as deemed
necessary by the customer or as applicable:”
Only those properties applicable to your product, or
deemed relevant by your customer need be considered.
Many of the IPAC-RS sections of the Guideline allow for
variation based on the needs of the supplier and the
customer and based on the component in question.
IPAC-RS Guideline FAQs
Q: This Guideline seems to require a lot of communication
with customers. Why is this so necessary?
A: OINDP components are critical to the functionality of
OINDP devices, which are very complex. Therefore, it is
critical that the supplier understand how the component
will be used, and what the needs of the customer are.
It is also important for the manufacturer to notify the
customer of changes. Seemingly “insignificant” changes
(e.g., change in cleaning agent, processing oil, or
packaging) can significantly affect the functionality of the
final OINDP device or its extractables/leachables profile.
IPAC-RS Guideline FAQs
Q: Does the Guideline require suppliers to perform
extractables testing?
A: NO! The Guidelines notes that “Extractables testing
should be performed by EITHER the OINDP
manufacturer, OR the OINDP component supplier, OR
the manufacturer with assistance from the supplier.”
This should be decided jointly by the supplier and their
customer.
Extractables testing need only be done on critical
components. The customer will identify these for the
supplier.
IPAC-RS Guideline FAQs
Q: How can I purchase a copy of the IPAC-RS
Guideline?
A: Contact Melinda Munos
[email protected]
Tel. 202-230-5118
OR
See www.ipacrs.com, which will post information on
the Guideline in the near future.
IPAC-RS Guideline FAQs
Q: Who do I contact if I have comments or questions
about the IPAC-RS Guideline?
A: Melinda Munos (IPAC-RS Secretariat)
[email protected]
Tel. 202-230-5118
Conclusion and Next Steps
Conclusion
• OINDP components are critical to the quality
and performance of OINDP
• IPAC-RS hopes that its GMP Guideline will
be helpful in standardizing and clarifying
quality expectations for OINDP component
suppliers
• IPAC-RS expects that OINDP manufacturers
will begin using the Guideline as an auditing
standard for their suppliers
• The IPAC-RS Guideline does not replace
supplier-customer communication and in fact
emphasizes the importance of such
communication
Next Steps
• U.S. Launch of Guideline and
education/training of OINDP manufacturers
and suppliers
• Consider development of an auditing
service, certification process, or conversion
of the Guideline to a Voluntary Consensus
Standard
Questions?
Acknowledgements
IPAC-RS Member Companies
Aradigm
AstraZeneca
Boehringer Ingelheim
Eli Lilly
GlaxoSmithKline
INyX
Kos
Nektar Therapeutics
Novartis
Novo Nordisk
Pfizer
Sanofi-Aventis
Schering-Plough
IPAC-RS Supplier QC Working Group
BoehringerIngelheim
Ray Oksala
Pfizer
Suzette McTigue
Eli Lilly
Ben Dai
Marcia Arentz
Presspart*
KOS
Barbara Falco, Chair
Bert Calvert
Susan Hall
Annette
Thompson
Nektar
Kenneth McCain*
ScheringPlough
Michael Lusty*
Novartis
Rainer Frueh
Novo Nordisk Lisa Erdös
Valois
Valerie Leveque,
Vice-chair
SanofiAventis
West
Linda Nield
Fran DeGrazio
Tom Gaspar
*Former WG members
Reviewers
• FDA
• PQG
• OINDP Suppliers
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3M
Bespak
Honeywell
Kinetics
Pfeiffer
Presspart
West
Valois
Special Thanks to
• Ashley McCreight (PQG)
• George Smith (FDA Office of Compliance) and
Jon Clark (FDA Office of Pharmaceutical Science)
• IPEC and IPEA, particularly Art Falk and Irwin
Silverstein
• The PQG, for this opportunity to present
Contact Information
IPAC-RS Secretariat
Melinda Munos
[email protected]
Tel. 202-230-5118