Technically Unavoidable Particles Profile (TUPPs) Guide

Transcription

1 Technically Unavoidable Particles Profile (TUPPs) Guide Priscilla Zawislak Global Regulatory Affairs Manager Ashland Inc. Chair Elect, IPEC-Americas 1

2 Agenda Introduction and Background Key Concepts and Definitions TUPPs Guide Overview 2

3 Introduction 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

4 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.

5 IMPORTANT DEFINITIONS AND CONCEPTS

6 Technically Unavoidable Particles 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

7 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

8 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

9 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

10 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

11 OVERVIEW

12 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

13 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

14 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

15 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

16 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

17 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)

18 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

19 Technically Unavoidable Particle Profile Examples 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 investigation process for unusual findings Heat sources frictional and added heat sources (drying, distillation, etc.) Discussion and trending of periodic particle types (risk assessment and decisions based on the observed trends) Discussion of the continuous improvement strategy/processes relative to visible particles and their formation List of lubricants, gasket materials, sealants, etc Discussion of how typical visible particles are minimized and controlled Discussion of the preventive maintenance (of process equipment AND visible particle control equipment) List of materials of construction

20 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

21 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

22 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

23 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? If found inside container, was/were the particle(s) found inside or outside the liner? Was/were the particle(s) found in the product or in a sample that was removed from the product? How is/are the container(s) opened, and is/are it/they cleaned prior to opening? Can a sample of the particle be provided to the manufacturer for evaluation? 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? Can a digital photo be provided? Dimensions/color/texture, etc. of particle(s) Are particles from a single excipient or a mixture of components when the particle was found? How is/are the container(s) sampled?

24 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

25 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

26 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

27 Is There a Safety Concern? 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

28 Conclusions 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

29 Acknowledgements Ann Van Meter Dow Chemical & Chair of IPEC-Americas GMP Committee

30 Thank You!