Vaccine Excipient Summary-Excipients Included in US
Vaccine Excipient Summary Excipients Included in U S Vaccines, by Vaccine In addition to weakened or killed disease antigens (viruses or bacteria), vaccines contain very small amounts of other ingredients – excipients Some excipients are added to a vaccine for a specific purpose These include: Preservatives, to prevent contamination
Qualification of Excipients for Use in Pharmaceuticals
Section 5 Excipient Supplier-User Negotiation Process: provides guidance on the development of an agreement between the excipient supplier and pharmaceutical user to define excipient quality requirements Glossary Terms defined in the glossary appear in bold the first time they are used in this document
Pharmaceutical Excipients - ABITEC
Excipient Classification *Statements are made by the best of our knowledge: EP—European Pharacopoeia, USP/NF—The United States Parmacopeia and The National Formulary, JPE—Japanese Pharmaceutical Excipients, USFA—United States Permitted Food Additive, JFSA—Japanese Standards for Food Additives, BP—British Pharmacopoeia, GRAS—Generally Recognized as Safe, IIG—Inactive Ingredient
Vaccine Excipients
Jan 15, 2021 · Vaccine Excipients www vaccinesafety edu updated January 15, 2021 page 1 Vaccine Excipients updated January 2021 Excipient Type Vaccine Name Vaccine Type Amount per 0 5mL dose
European Regulations for Excipients and the application of
2 3 For each excipient from each manufacturer used, the manufacturing authorisation holder should identify the risks presented to the quality, safety and function of each excipient from its source —be that animal, mineral, vegetable, synthetic, etc —through to its incorporation in the finished pharmaceutical dose form
The IPEC Risk Assessment Guide for Pharmaceutical Excipients
As part of the excipient evaluation and qualification process, the drug manufacturer/ MAH holder should perform risk assessments to evaluate the excipient supplier, quality systems, manufacturing operations, etc Risk assessments by excipient users are performed by taking into account: The type of excipient
EU Excipient Risk Assessment Guidelines – Practical
In terms of content, the EU Excipient Risk Assessment Guidelines address both the intended use and source of excipients The main topics are described in chapter 2 to 4, which cover: • Determining appropriate GMP based on excipient type and use (chapter 2) • Determining the excipient manufacturer’s risk profile (chapter 3)
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The IPEC
Risk Assessment Guide
for PharmaceuticalExcipients
Part 1 Risk Assessment for
Excipient Manufacturers
First Version
20172014
Copyright © 2017 The International Pharmaceutical Excipients Council
Page 2 of 43
This document represents voluntary guidance for the pharmaceutical excipient industry and the contents should not be interpreted as regulatory requirements. Alternative approaches to those described in this guide may be implemented.FOREWORD
International Pharmaceutical Excipients Council (IPEC) is an international industry association formed in 1991 by manufacturers, distributors and end-users of excipients. At the time of writing there are regional pharmaceutical excipient industry associations including the Americas, Europe,Japan, China, and India
of international excipient standards, the introduction of useful new excipients to the marketplace, and the development of best practice and guidance concerning excipients.IPEC has three major stakeholder groups;
1. Excipient manufacturers and distributors, who are considered suppliers in this
document2. Pharmaceutical manufacturers, who are called users
3. Regulatory authorities who regulate medicines
Suppliers
Regulatory
Authorities
Users IPEC This document offers best practice and guidance in risk assessment related to excipients covering the principles of quality risk management, including risk assessment methodologies providing an overview on methods in the ICH Q9 guideline. It includes areas where risk assessment may be used by the excipient manufacturer in the lifecycle of excipient. Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 3 of 43
TABLE OF CONTENTS
FOREWORD .................................................................................................................................. 2
ACKNOWLEDGEMENTS ............................................................................................................ 5
1. INTRODUCTION ................................................................................................................... 6
1.1. Purpose ........................................................................................................................... 6
1.2. Scope ............................................................................................................................ 6
1.3. Background .................................................................................................................... 6
1.4. Layout 7
2. PRINCIPLES OF RISK ASSESSMENT AND MANAGEMENT......................................... 8
2.1. Phase I: Risk Assessment ............................................................................................... 8
2.2. Phase 2: Risk Control .................................................................................................... 9
2.3. Phase 3: Risk Communication ...................................................................................... 9
2.4. Phase 4: Risk Review .................................................................................................. 10
2.5. Documentation ............................................................................................................. 10
3. RISK ASSESSMENT METHODS ....................................................................................... 10
3.1. Failure Mode Effects Analysis (FMEA) ...................................................................... 11
3.2. Failure Mode, Effects and Criticality Analysis (FMECA, aka, FMEA) ...................... 11
3.2.1. Establish Clear Definitions .......................................................................................... 11
3.2.2. Risk score matrix ......................................................................................................... 12
3.3. Fault Tree Analysis (FTA) ........................................................................................... 12
3.4. Hazard Analysis and Critical Control Points (HACCP) .............................................. 13
3.4.1. Describe the Product, Intended Use and Process ......................................................... 13
3.5. Hazard Analysis and Risk-Based Preventive Controls (HARPC) from 21CFR117
Subpart C ...................................................................................................................... 14
3.6. Hazard Operability Analysis (HAZOP) ....................................................................... 14
3.7. Preliminary Hazard Analysis (PHA) ............................................................................ 15
3.8. Risk Ranking and Filtering .......................................................................................... 15
4. RISK ASSESSMENT BY EXCIPIENT MANUFACTURER .......................................... 16
4.1. Risk Assessment Documentation ................................................................................. 16
4.2. Areas Requiring Risk-Based Decision Making ........................................................... 16
4.2.1. Hygienic Practices ....................................................................................................... 17
4.2.2. Building and Facilities ................................................................................................. 20
4.2.3. Equipment Construction .............................................................................................. 22
4.2.4. Equipment Maintenance .............................................................................................. 23
4.2.5. Utilities ........................................................................................................................ 25
4.2.6. Water ........................................................................................................................... 26
4.2.7. Air Handling Systems .................................................................................................. 28
4.2.8. Special Environments .................................................................................................. 29
4.2.9. Cleanliness and Sanitary Conditions ........................................................................... 30
4.2.10. Pest Control ................................................................................................................. 32
4.2.11. Planning for excipient realization ................................................................................ 33
Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 4 of 43
4.2.12. Customer Communication ........................................................................................... 34
4.2.13. Purchasing Process ...................................................................................................... 34
4.2.14. Verification of Purchased Product ............................................................................... 37
4.2.15. Preservation of Product ............................................................................................... 38
4.2.16. Excipient Packaging Systems ...................................................................................... 39
4.2.17. Control of Monitoring and Measuring Equipment ...................................................... 40
4.2.18. Reworking ................................................................................................................... 40
5. REFERENCES ...................................................................................................................... 42
Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 5 of 43
ACKNOWLEDGEMENTS
This guide was developed by representatives of many of the member companies of the InternationalPharmaceutical Excipients Council of the Americas (IPEC-Americas®), an industry association
headquartered in Arlington, Virginia whose principal members consist of excipient manufacturers,
distributors, and users. The company representatives who worked on this guide are listed below:IPEC-Americas Members
Ann Van Meter, AVM Enterprises
Bretta Lichtenhan, Millipore Sigma
Dale Carter, J.M. Huber, Engineered Materials
Dave Schoneker, Colorcon
David Klug, Sanofi
George Collins, Vanderbilt Chemicals, LLC
Heather Sturtevant, J&J Consumer Healthcare
Irwin Silverstein, IBS Consulting in Quality LLC
Kathy Ulman, KLU Consulting LLC
Katrina Elia, SPI Pharma
Meera Raghuram, Lubrizol Advanced Materials, Inc.
Pam Malcontento, Univar USA Inc.
Priscilla Zawislak, The Dow Chemical Company
Sydney Goode, PFAR Consulting
Terry Berger, Genentech
Tina Jones, Grace
Chandra Sekhar, Chandra V. Sekhar Consulting
Jane Bono, Ashland Specialty Ingredients
Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 6 of 43
1. INTRODUCTION
1.1. Purpose
The primary intent of the IPEC Risk Assessment Guide for Pharmaceutical Excipients (RAG) is to provide
a systematic and scientifically sound methodology for the evaluation of risk to excipient quality and to
facilitate more effective and consistent risk-based decisions by excipient makers, distributors, and users.
Guidance is provided herein ofrom the perspective of an excipient manufacturer or distributor.1.2. Scope
The scope of this guide is to provide excipient suppliers with an overview of risk assessment tools, and
resources that they can use, when conducting risk assessments required by both NSF/IPEC/ANSI 3631 and
2 excipient GMP standards, in order to identify and control for potential risks to excipient
quality. The guide provides an overview of: 1) quality risk management, 2) the scientific principles of risk
identification and assessment and 3) an outline of the process and use of appropriate risk assessment
methodologies. In addition, the guide identifies areas where risk assessments requirements are found in
both the NSF/IPEC/ANSI 363 documentation to demonstrate adequacy of risk assessment and GMP controls.The IPEC Risk Assessment Guide Part 1 is designed to provide excipient manufacturers and distributors
with a common starting point to evaluate risks and develop risk management plans, as appropriate. The
guide can help users in assessing their suppliers risk assessment plans. We expect to include additional
sections to the risk assessment guide in the future and this edition reflects the first part.1.3. Background
IPEC has developed and promoted the implementation of appropriate and scientifically valid voluntary industry guides for excipients3 for many yearsmakers, distributors and users makes this association uniquely positioned to understand the underlying risks
to excipient quality. IPEC guides were developed to address these risks as they were identified to the
is to ensure that excipients meet the highest appropriate standards for quality,safety and functionality throughout their manufacturing process and supply chain. The use of risk
management principles applied to excipients furthers this cause. In the current regulatory environment surrounding excipients, pharmaceutical manufacturers are underincreasing pressure to develop better knowledge of their excipients and excipient supply chain.
Pharmaceutical manufacturers are required to ensure that excipients used in the drug products are fit for
their intended use. The diversity of excipient manufacture, type of material and application means that a
patient safety. Supplier led risk assessments to determine the threats to quality and patient safety are
mandated in , GMP and GDPs and the American National Standard GMP for Pharmaceutical Excipients, NSF/IPEC/ANSI 363. Both of these standards utilize quality risk-management principles toensure that proportionate controls are applied in manufacturing and distribution to produce and deliver
excipients that are safe, of appropriate quality and of consistent composition. These voluntary standards
1 NSF/IPEC/ANSI 363 -2014 Good Manufacturing Practices (GMP) for Pharmaceutical Excipients
2 Certification Standards for Pharmaceutical Excipients: Good Manufacturing Practices, Good
Distribution Practices, 2012
3 IPEC Guides are available as a free download from https://ipecamericas.org/ipec-store (Americas) and
http://www.ipec-europe.org/page.asp?pid=59 (Europe). Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 7 of 43
using risk assessment tools are mirrored by the authorities in Europe with the Falsified Medicines directive
(FMD) legislation (2011/62/EU) requiring Manufacturing Authorization Holders (MAH)4 to perform anddocument a formalized risk assessment and consider the source and intended use of excipients as well as
previous instances of quality defects. As part of the excipient evaluation and qualification process, the drug
manufacturer/ MAH holder should perform risk assessments to evaluate the excipient supplier, qualitysystems, manufacturing operations, etc. Risk assessments by excipient users are performed by taking into
account:The type of excipient
The manufacture of the excipient
The quality history of the excipient supplier and the reliability and integrity of the supply chain The use of the excipient in the finished product and its route of administration be accessed on the IPEC Europe web site (IPEC Europe Guidelines) which was created to give excipientusers and suppliers additional information and guidance to accurately complete a risk assessment
specifically to meet the EU FMD requirements.5This guide is intended to provide excipient manufacturers, distributors and users with guidance on risk
assessment methodologies and assessment techniques for identifying and assessing potential risks.1.4. Layout
This guide includes the following sections:
Principles of risk assessment and management
Risk assessment methods, including an overview of basic risk facilitation methods as outlined in the ICH Q96 guideline Risk assessment by excipient manufacturer, including requirements described in NSF/IPEC/ANSI363 and
7 is noted by the use
of bold type with no underline.4 EU Guidelines of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate good
manufacturing practice for excipients of medicinal products for human use (QJ 2015/C 95/02)5 - Guidelines of 19 March 2015 on the formalised risk assessment for
ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use
6 International Conference on Harmonisation, ICH Q9: Quality Risk Management, November 2005.
7 International Pharmaceutical Excipient Council Glossary: Glossary of Official Definitions for Excipients.
Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 8 of 43
2. PRINCIPLES OF RISK ASSESSMENT AND MANAGEMENT
Risk assessment is a basic principle to support decision making in the NSF/IPEC/ANSI 363 and
ds, where it is used to define the GMP controls necessary to mitigate those risks thathave been identified as potentially posing a threat to excipient quality. The implementation of specific GMP
controls is dependent upon the evaluation of risk to the excipient quality. Performing risk assessments in
accordance with a defined quality risk management procedure ensures a consistent assessment of risk and
facilitates communication of the identified risks throughout the organization. A documented risk assessment
also provides for periodic review of the risk to verify the output of the assessment has remained valid.
Quality risk management requires a documented science-based evaluation of risk with focus on quality of
the excipient and potential impact of the excipient on patient safety. This facilitates conformance to the risk
assessment requirements of the standard.The extent of the assessment of risk should be commensurate with the hazard posed to excipient quality. If
a section in the GMP standard does not apply, then justification should be documented.The Quality Risk Management procedure should address the four phases involved with assessing a potential
hazard as discussed below.2.1. Phase I: Risk Assessment
The first phase, risk assessment, begins with a well-defined problem definition, referred to as risk
identification or hazard identification. Identification of the risk can be framed by asking the following
fundamental questions:What might go wrong (the hazard)?
What are the consequences of the hazard (severity)? What is the likelihood it will go wrong (probability)? Can the presence of the hazard be identified (detectability)?Hazard i
consequences. Examples of hazard identification are the failure of a valve that results in contamination of
the excipient, poor housekeeping that allows accumulated dust to become airborne and settle on the exposed
excipient, the presence of rodents in the facility, etc. Once the hazard has been identified, it is appropriate
to gather a team of subject matter experts and risk assessment experts to perform the assessment and develop
the control strategy. During this phase, background information such as historical data, theoretical analysis,
informed opinions and stakeholder concerns, is assembled.Following hazard identification, risk analysis provides an estimation of the risk associated with the
identified hazard. Depending upon the risk analysis tool selected, the analysis is either a qualitative or
quantitative process that links the severity of the harm with the probability of occurrence. Certain tools also
add the ability to detect the harm (detectability) in order to provide an estimate of the magnitude of the risk.
Once the risk analysis has been completed, risk evaluation is used to compare the level of perceived risk
against established risk criteria. Risk evaluation considers the response to the fundamental questions;
severity, probability of occurrence, and, where assessed, detectability. The risk criteria determine the need
to implement risk control or risk reduction.The quality of a risk assessment rests on the data used. Disclosing the assumptions and sources of
uncertainty enhances confidence in the evaluation and identifies its limitations. Typical sources of
uncertainty include gaps in:Excipient knowledge and process knowledge
Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 9 of 43
Understanding of potential harm to the pharmaceutical manufacturer from an excipient used in a drug product (such as the impact on manufacturing the drug product, impurities, stability, etc.) Understanding of potential harm to the patient from an excipient used in a drug product (such as affecting the drug bioavailability, patient acceptance, presence of contaminants, etc.)The output of phase 1 is a qualitative or quantitative level of risk based on the potential hazard(s) identified.
2.2. Phase 2: Risk Control
In the second phase, risk control, the decision is made to either accept the level of risk or take measures to
reduce the risk to an acceptable level. The following questions help guide this effort: Is the risk higher than a level deemed acceptable? What measures will reduce or eliminate a risk that exceeds an acceptable level? What is the proper balance between the benefit, risk and resources needed to affect reduction? Will a new risk be introduced as a consequence of risk reduction? Risk acceptance recognizes that the level of risk is not high enough to negatively impact either the pharmaceutical customer or their patients. Where the risk may impact the pharmaceutical customer orpatient, risk reduction should be considered. Reduction measures can reduce the probability, or increase
detectability or any combination thereof. Risks may be reduced through measures such as a change in materials, process, equipment, personalprotective equipment (PPE) etc. For example, the risk of transmissible spongiform encephalopathy (TSE)
can be mitigated by sourcing the animal derived raw material from a lower risk supplier or switching to a
non-animal source. Changes should be evaluated based on the IPEC Significant Change Guide8.Detectability might be improved through more reliable or sensitive quality control testing; implementation
of in-process testing, either in-line or at-line; expansion of finished excipient sampling, etc. The ability to
detect the consequence of a hazard may reduce the potential for non-compliant excipients being shipped to
a customer.Once a risk reduction decision has been made, it is appropriate to repeat the risk analysis in order to assess
whether implementation of the risk reduction measures introduced any new risks to the excipient. Thereview of the risk analysis results should show reduction of the risk to acceptable level or one that is
commensurate based upon cost/benefit analysis. The impact of any significant change on the risk
assessment assumptions and results should be evaluated consistent with change control processes and, if
necessary, appropriate actions should be taken to mitigate further risks.2.3. Phase 3: Risk Communication
The third phase, risk communication involves communication of the conclusions from the first two phases,
and involves sharing of the risk assessment and risk control with interested and affected parties. Interested
parties often include operators and department personnel within the site and company that implement the
risk reduction measures or are potentially impacted by them. Of particular importance is the communication
of risk reduction activities for evaluation under management of change (change control). Impacted activities
may include changes in production, quality control, quality assurance, internal audit(s), marketing, etc.
External interested parties include customers that may be impacted by the risk and regulators who are aware
of the risk.8 The International Pharmaceutical Excipients Council Significant Change Guide, Third Revision, 2014.
Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 10 of 43
2.4. Phase 4: Risk Review
The final step in quality risk management is risk review. The risk assessments completed to comply with
NSF/IPEC/ANSI 363 and standards should be periodically reviewed in order to ensure that their conclusions remain valid. The quality risk management procedure should include a maximum timeinterval for performing a risk review. The review should examine any changes to the excipient quality or
conformance to the standard(s) since the original risk assessment or previous risk review. More frequent
reviews should be performed in response to: Customer complaints resulting from the risk that was assessed Finished excipient test failure for a risk that was mitigatedDeviations which can impact quality
Significant changes, where appropriate
Change to regulatory requirement or customer expectation related to the risk2.5. Documentation
The quality risk management procedure should describe documentation required to demonstrate that therisk was evaluated in accordance with the procedure. NSF/IPEC/ANSI 363 requires that a risk assessment
be used to justify any section of the standard that is not applicable. Documentation of such risk assessments
need only provide the rationale as to why the section does not apply.The objective of documentation is to show that a systematic assessment was conducted by knowledgeable
individuals and provides the basis for the decision made. The common supporting documentation for a risk
assessment, regardless of the assessment technique, should include: Members of the risk assessment team along with their role on the teamMeeting agendas
Meeting minutes
Outcome of risk assessment activities
Communication of the risk mitigation under change control.3. RISK ASSESSMENT METHODS
There are many methods for performing a risk assessment. This guide will refer to the techniques listed in
ICH Q9:
1. Failure Mode Effects Analysis (FMEA)
2. Failure Mode Effects and Criticality Analysis (FMECA, aka FMEA)
3. Fault Tree Analysis (FTA)
4. Hazard Analysis and Critical Control Points (HACCP)
5. Hazard Analysis and Risk-Based Preventive Controls (HARPC)
6. Hazard Operability Analysis (HAZOP)
7. Preliminary Hazard Analysis (PHA)
8. Risk Ranking and Filtering
The common elements of each technique discussed below are:1. A clear definition of the goal of the assessment, including the scope of the hazard, real or potential,
that is being assessed. Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 11 of 43
2. A team typically comprised of a facilitator, a team lead, and functional experts, as appropriate.
Dividing the assessment into unit operations can facilitate the evaluation of an entire manufacturing
process.3. Risk assessment documentation sufficient to demonstrate that relevant site procedures were
followed.3.1. Failure Mode Effects Analysis (FMEA)
FMEA is used to assess the potential failure modes of equipment and facilities in order to identify the
potential impact of failure on product or process. FMEA is a qualitative tool typically used to identify the
root cause of risks and develop mitigation to prevent failure. A key difference between FMEA and FMECA
is that FMECA extends the assessment by assigning a rating to the criticality of the hazard, the severity,
probability of occurrence, and detectability. Assigning a rating facilitates the prioritization of hazards,
through the development of a risk score, which allows one to prioritize mitigation efforts and to make an
objective decision on risk tolerance. FMEA has been widely supplanted by FMECA for the purpose of quantifying and prioritizing risk. Sincethe fundamentals of FMECA rests on those of FMEA, the guide will only provide details on FMECA; often
referred to in the literature as FMEA. Therefore, further reference to FMEA in this guide will refer to
Failure Mode, Effects and Criticality Analysis.
3.2. Failure Mode, Effects and Criticality Analysis (FMECA, aka, FMEA)
Components of the FMECA are:
Severity: if a failure were to occur, what effect would that failure have on the product quality and on the patient (if any)? Probability of occurrence: how likely is it for a particular failure to occur? Detectability: what mechanisms are in place (if any) to detect a failure if it were to occur?Each of the above metrics require clear definitions and a corresponding scale to rank or score the projected
impact (i.e. a scale for severity; probability; and detectability). A composite score can to be calculated (e.g.
severity multiplied by probability multiplied by detectability) and matrixed so that final team
recommendations are based on a calculated risk ranking.This technique lends itself to a quantitative assessment of the risk resulting from equipment and facilities
and allows for the analysis oexcipient manufacturingprocess. However, FMEA can only assess a single mode of failure not a combination of failure modes. This
technique is useful for assessing the impact of potential failures and the development of effective preventive
measures. FMECA is useful during the design process as a bottom up analysis.3.2.1. Establish Clear Definitions
As described in section 2.1 of this guide, there are three components to a risk assessment: severity,
probability, and detectability. The definitions for the various rankings of severity, probability, and
detectability should be clearly articulated in the assessment documentation. Copyright © 2017 The International Pharmaceutical Excipients CouncilPage 12 of 43
The multiplication of the ratings for severity, probability, and detectability produce a risk priority number
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