Technically Unavoidable Particles
Profile (TUPPs) Guide
Priscilla Zawislak
Global Regulatory Affairs Manager – Ashland Inc.
Chair –Elect, IPEC-Americas
www.ipecamericas.org1
2
Agenda
• Introduction and Background
• Key Concepts and Definitions
• TUPPs Guide Overview
• Technically unavoidable particles are present in excipients
• A level of “ZERO” is not achievable
• The number of process inherent, technically unavoidable particles
is very small compared to the batch size for most excipients
• Six sigma or higher performance level is the norm
• Incremental improvements yield relatively minor results
• Step change improvements in performance may not be possible
and would generally be quite expensive
• Basis documents:
– IPEC PQG GMP Guide
– ICH Q9 – Quality Risk Management
Introduction
Background
• Previous guidance from IPEC, compendia or regulators has not dealt
with this issue effectively
• Materials, and in some cases entire excipient lots, are rejected
unnecessarily
• Users and makers spend time, money and resources investigating
particles that are technically unavoidable and do not pose a risk to
patient safety
• In many instances, the identity and origin of these particles are known
and have been extensively investigated by the excipient
manufacturer.
• The particles are inherent to the manufacturing process or excipient
• The Technically Unavoidable Particle Profile Guide provides a pathway
to share identity and origin data for particles typically found in
excipients.
IMPORTANT DEFINITIONS
AND CONCEPTS
• Particles that are visibly different from the bulk of the material when viewed with the
naked eye within the container or against a
suitable background (examples are size,
shape, color, number, texture ), AND:
– Are inherent to the excipient manufacturer’s
process, product or raw materials
– Are technically unavoidable
Technically Unavoidable
Particles
Technically Unavoidable
• The non-intended presence of a small quantity of particles, stemming from impurities of natural or synthetic ingredients, the manufacturing process, storage, migration from packaging, which is technically unavoidable in good manufacturing practice*
• AND do not pose risk to patient safety
* Definition contained in Article 17 of the “Regulation (EC) No. 1223/2009 for the European Parliament and of the Council of 30 November 2009 on cosmetic products”
Technically Unavoidable
Particle Profile• The Technically Unavoidable Particle Profile (TUPP)
documents the excipient maker’s knowledge of:
– the types of technically unavoidable particles (TUPS)
– their origin for a particular manufacturing process or product
• The TUPP includes results of prior investigations of various particles, results of risk assessments, raw material characterization, unavoidable particles from product packaging, etc.
• The TUPP should exist in a form that can be shared
• The discussion of the TUPP best occurs during excipient qualification to avoid future complications
Technically Unavoidable
Particle Profile, continued• Although significant information may exist for TUPs and their
origin; specifications or limits cannot and/or should not be
expected on Certificates of Analysis.
• The insignificant number of particles relative to batch size
and the intermittent nature of their observance make a
specification unrealistic and unreliable
• Where aesthetically unacceptable, limits on TUPs (and
methods) may be an item for agreement between the
user and excipient maker
– Excursions above agreed TUP limits cannot always be prevented as
the low levels and low detectability may be beyond the capability
of the process
Foreign/Atypical particles
• These particles are not consistent with the technically
unavoidable particle profile
• Atypical particles may not have been previously encountered
or identified; therefore, require further investigation to determine
whether they are foreign or inherent to the process or product.
– Must be investigated on a case by case basis
– Investigation results should be shared with the user
– Depending on the results of the investigation and the user’s risk
assessment, an acceptance decision must be made by the user (In
accordance with the principles of ICH Q9 – Quality Risk Assessment)
– If the investigation indicates the presence of foreign contamination,
the material should be rejected and returned to the excipient
supplier
– The final disposition would be the excipient supplier’s responsibility
OVERVIEW
Scope and Basis
• The IPEC-Americas Technically Unavoidable Particle Guide is applicable to excipients intended for use in drugs
• Patient safety is paramount
• Science and risk-based approaches
• Out of scope of the guide are excipients intended for:
– Parenteral or ocular use
– Sterile and/or pyrogen free
• The guide is not meant to deal with foreign contamination/adulteration which can be a failure of Good Manufacturing Practices (GMPs), and is unacceptable
• This guide is not a stand alone document
– A predicate requirement is compliance with the IPEC PQG GMP Guide
– The principles of risk assessment established in ICH Q9 – Quality Risk Management should be considered in decision making
General Principles
The guide • Is not intended to condone poor GMPs
• Assumes full compliance with appropriate GMPs and is not applicable to objectionable particles resulting from contamination or adulteration
• Encourages a risk-based approach for evaluating visible particles in excipients
• Provides for the sharing of information by excipient manufacturers with their pharmaceutical customers, for the purpose of understanding the technically unavoidable particles
• Provides an approach for investigation of rare occurrences when a previously unobserved particle is found by the end user
General Considerations
• The guide is not about avoiding responsibility of GMPs – quite
the contrary
• Acknowledgement of the concept of “technically unavoidable
particles (TUPs)” assumes implementation of available
technologies to mitigate particle formation and inclusion in
excipients
• When building in mitigation strategies for new plants or
retrofitting existing plants
– Do what is possible and economically viable
• When employing appropriate mitigations, the guide will aid
both users and makers in determining path forward regarding
those particles that will always be present– Reality is that this phenomenon is not new – TUPs HAVE always been in
excipients and to some extent WILL ALWAYS be in excipients
Risk assessment
• When aware that a product / process could result in TUPs, an
excipient manufacturer should perform/document a risk
assessment to identify and assess the types of particles that may
be present
• Common risk assessment models are available for this purpose
– Some examples of risk assessment models are characterized in ICH
Q9 – Quality Risk Management
• Makers should be willing to share the results of risk assessment
– The method for sharing this information should be determined
between the maker and the user, since some of this information
may be considered confidential
• Excipient users should evaluate the information provided using the concepts of the guide and then evaluate the risk to patient
safety as it relates to their application
Types of TUPs
• Charred particles - discolored due to exposure to heat
• Particles representing process materials of construction due to normal and reasonably expected wear
• Particles consistent with routinely used gaskets, seals, filters, etc.
– Equipment components are known to wear and are therefore routinely replaced on a preventive maintenance schedule. Thus, particle shedding should be considered a normal part of the process
– Materials of construction for these items should be food grade or food contact approved or otherwise justified and of appropriate construction
• Particles containing traces of lubricants, greases and oils or like materials may be discolored – these too should be food grade or food contact approved where possible
Types of TUPs, continued
• Packaging component particles – These particles are small, unavoidable, materials of
construction of the packaging, e.g. cardboard or paper shedding.
• Misshapen or morphologically distinct particles, including but not limited to: – Compressions or agglomerations of particles
– Elongated and/or tangled particles
– Flakes
• Color variation inherent to the product
• Intrinsic components carried through from raw materials (mined materials or those sourced from natural products)
Technically Unavoidable
Particle Profile• The excipient manufacturer has an obligation
to help users understand the nature of particles observed in the excipient, and to ensure that these particles are not foreign contamination
• Assistance could be as simple as exchanging information indicating that the particle is consistent with the manufacturing process and would therefore considered technically unavoidable
Technically Unavoidable
Particle ProfileExamples of some of the types of information or data that may
be considered as inputs for the development of the TUPP
Photographs, chemical analysis, physical
characterization, and other forms of
characterization as applicable
Discussion of the continuous improvement
strategy/processes relative to visible
particles and their formation
Discussion of the investigation process for
unusual findings
List of lubricants, gasket materials,
sealants, etc
Heat sources – frictional and added heat
sources (drying, distillation, etc.)
Discussion of how typical visible particles
are minimized and controlled
Discussion and trending of periodic
particle types (risk assessment and
decisions based on the observed trends)
Discussion of the preventive maintenance
(of process equipment AND visible particle
control equipment)
List of materials of construction
Manufacturer’s Expectations
• An excipient manufacturer should understand and have
available a Technically Unavoidable Particle Profile of the
known technically unavoidable or inherent particles for a
particular excipient
• The scope and complexity of the profile depends on the
excipient
• For those excipients that rarely exhibit these types of particles,
the TUPP could be as simple as a statement that they are not
normally present
• For excipients that are likely to contain technically unavoidable
particles, either through process related formation, raw material
introduction or morphologically distinct particles of product, the TUPP will likely be more comprehensive
Manufacturer’s Expectations
• Consistent with GMPs, in-process sources of particles should be
identified and where possible mitigation strategies and
technologies employed
• Once a mitigation technology is employed, it should be
properly maintained to ensure continued effectiveness
• Any remaining particles would be characterized as technically
unavoidable if the manufacturer has met the obligations of
GMP
• Periodic evaluation of mitigation strategies and technologies
and continuous improvement initiatives should be included as
part of the GMP quality system related to typical visible particles
Atypical Particles
• Particles not part of a TUP profile are expected to undergo a
full investigation
• Particles not part of a TUP profile(i.e. not previously observed)
but known to be consistent with manufacturing equipment,
facility, gaskets, lubricants materials of construction, should the
acceptable based on a documented risk assessment
• When an investigation identifies a new type of technically
unavoidable particle, the results should be included in TUPP
• When an investigation identifies something other than a
technically unavoidable particle or particle inherent to
process materials of construction:
– Return of the material would be expected
– The excipient manufacturer determines the appropriate
disposition of the material
Investigation of Atypical Particles
• The more information provided by the user, the easier and faster an investigation can be
completed on the maker side, and vice versa.
• It is the user’s responsibility to provide as much information as possible about how the
particle was found such as:
Has the particle been analyzed or has the composition been determined?
How is/are the container(s) opened, and is/are it/they cleaned prior to opening?
If found inside container, was/were the particle(s)
found inside or outside the liner?
Can a sample of the particle be provided to the
manufacturer for evaluation?
Was/were the particle(s) found in the product or in a sample that was removed from the product?
Was/were the particle(s) found inside the excipient container or during screening/use?
Are multiple or only one suppliers asked to provide information? if only one, could they be suspected as the source?
Are particles from a single excipient or a mixture of components when the particle was found?
Can a digital photo be provided? How is/are the container(s) sampled?
Dimensions/color/texture, etc. of particle(s)
User Evaluation Criteria
• The purpose of the guide is to provide understanding of the
scope of normal, inherent and technically unavoidable
particles between excipient manufacturers and users.
• When particles are observed by a user, the guide describes
the expectations around the exchange of information that
would constitute an investigation and lead to the proper disposition of affected product
• The disposition should not normally result in the rejection of
material when the observed particles are within the range of
normal or typical particles previously described as likely to be
observed with the excipient
User Evaluation
• When a visible particle is observed by the user, the excipient
manufacturer should be contacted to identify the particle as
well as its source
• This exchange of information between user and maker may
take the form of a TUPP or a report of the result of the maker’s
evaluation of the particle
• This should provide sufficient information to allow the user to
make a risk assessment for their product or application
• If it is determined that the particle is typical and technically
unavoidable, it is important for users to understand that these
particles have historically been present in excipients, and generally pose no risk to patient safety
User Evaluation, continued
• Unique issues related to TUPs that may be involved with the application or dosage form should be discussed with the supplier
• Reduced levels of TUPs necessary to support the application or dosage form should also be discussed with the supplier
• When possible, potential reduction in TUPs may require additional manufacturing steps
• Additional manufacturing steps may – change the performance characteristics of the excipient,
– introduce new or different technically unavoidable particles
– increase costs
• In many cases, reduced levels of TUPs will not be technically or economically achievable
• This is one of the most important questions to answer
• Usually TUPs inherent to the process are safe and there is no risk
– The inherent TUPs may be the same excipient possibly discolored
– It may be the starting raw material
– The TUPs may be part of the normal wear and tear of the equipment
or packaging and can be safely removed
– REMEMBER: They have ALWAYS been present
• There may be instances when particles could pose a safety
concern
– Usually this is not inherent to the excipient but is contamination
– This tends to be rare but possible
– This is a breach of GMP
• Ongoing communication between Maker and User is the key to
quickly resolving questions around visible particles
Is There a Safety Concern?
• The IPEC-Americas Technically Unavoidable Particle Profile Guide provides a path for identification of particles and guidance for risk-based decision making
• IPEC recommends use by Makers & Users when they discuss TUPs
• Honest, transparent discussions at all phases of development must be the norm between maker and users
• Risk-based approaches to process inherent, technically unavoidable particles
Conclusions
Acknowledgements
• Ann Van Meter – Dow Chemical &
Chair of IPEC-Americas GMP
Committee
Thank You!
