NSF International Standard /

American National Standard

NSF/IPEC/ANSI 363 - 2014

Good Manufacturing Practices
(GMP) for Pharmaceutical
Excipients
NSF International, an independent, not-
for-profit, non-governmental organization,
is dedicated to being the leading global
provider of public health and safety-
based risk management solutions while
serving the interests of all stakeholders.

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This Standard is subject to revision.
Contact NSF to confirm this revision is current.

Users of this Standard may request clarifications and

interpretations, or propose revisions by contacting:
Chair, Joint Committee on Pharmaceutical Excipients
c/o NSF International
789 North Dixboro Road, P. O. Box 130140
Ann Arbor, Michigan 48113-0140 USA
Phone: (734) 769-8010 Telex: 753215 NSF INTL
FAX: (734) 769-0109
E-mail: [email protected]
Web: http://www.nsf.org
 NSF/IPEC/ANSI 363–2014

NSF International Standard/

International Pharmaceutical
Excipients Council/
American National Standard
for Pharmaceutical Excipients –

NOT FOR Good Manufacturing

Practices (GMP) for

DISTRIBUTION
Pharmaceutical Excipients

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Standard Developer
NSF International

NSF International

Designated as an ANSI Standard

November 17, 2014
American National Standards Institute

i
Prepared by
The NSF Joint Committee on Pharmaceutical Recipients

Adopted
December 2014

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OR SALE
Published by

NSF International
PO Box 130140, Ann Arbor, Michigan 48113-0140, USA

For ordering copies or for making inquiries with regard to this Standard, please reference the designation
“NSF/IPEC/ANSI 363 – 2014.”

Copyright 2014 NSF International

Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any
means, electronic or mechanical, including photocopying and microfilm, without permission in writing from
NSF International.

Printed in the United States of America.

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Disclaimers
1

NSF, in performing its functions in accordance with its objectives, does not assume or undertake to
discharge any responsibility of the manufacturer or any other party. The opinions and findings of NSF
represent its professional judgment. NSF shall not be responsible to anyone for the use of or reliance
upon this Standard by anyone. NSF shall not incur any obligation or liability for damages, including
consequential damages, arising out of or in connection with the use, interpretation of, or reliance upon
this Standard.

NSF Standards provide basic criteria to promote sanitation and protection of the public health. Provisions
for mechanical and electrical safety have not been included in this Standard because governmental
agencies or other national standards-setting organizations provide safety requirements.

Participation in NSF Standards development activities by regulatory agency representatives (federal,

local, state) shall not constitute their agency's endorsement of NSF or any of its Standards.

Preference is given to the use of performance criteria measurable by examination or testing in NSF
Standards development when such performance criteria may reasonably be used in lieu of design,
materials, or construction criteria.

The illustrations, if provided, are intended to assist in understanding their adjacent standard requirements.
However, the illustrations may not include all requirements for a specific product or unit, nor do they show

NOT FOR
the only method of fabricating such arrangements. Such partial drawings shall not be used to justify
improper or incomplete design and construction.

Unless otherwise referenced, the annexes are not considered an integral part of NSF Standards. The

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annexes are provided as general guidelines to the manufacturer, regulatory agency, user, or certifying
organization.

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The information contained in this Disclaimer is not part of this American National Standard (ANS) and has not been
processed in accordance with ANSI’s requirements for an ANS. Therefore, this Disclaimer may contain material that
has not been subjected to public review or a consensus process. In addition, it does not contain requirements
necessary for conformance to the Standard.

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Contents

1 General ............................................................................................................................................. 1
1.1 Introduction ................................................................................................................................. 1
1.2 Scope ......................................................................................................................................... 1
1.3 Purpose ...................................................................................................................................... 2

2 Reference documents ....................................................................................................................... 2

2.1 Normative references .................................................................................................................. 2
2.2 Informational references.............................................................................................................. 2

3 Definitions ......................................................................................................................................... 3

4 Quality management system ............................................................................................................. 7

4.1 General requirements ................................................................................................................. 7
4.2 Documentation requirements ...................................................................................................... 9
4.3 Change control ......................................................................................................................... 10

5 Management responsibility .............................................................................................................. 11

5.1 Management commitment ......................................................................................................... 11
5.2 Customer focus......................................................................................................................... 11
5.3 Quality policy ............................................................................................................................ 11

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5.4 Planning.................................................................................................................................... 12
5.5 Responsibility, authority, and communication ............................................................................ 12
5.6 Management review .................................................................................................................. 13

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6 Resource management ................................................................................................................... 14
6.1 Provision of resources ............................................................................................................... 14
6.2 Human resources...................................................................................................................... 14
6.3 Infrastructure............................................................................................................................. 15
6.4 Work environment ..................................................................................................................... 17

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Excipient realization ........................................................................................................................ 18
7.1 Planning of excipient realization ................................................................................................ 18
7.2 Customer-related processes ..................................................................................................... 19
7.3 Design and development (out of scope) .................................................................................... 19
7.4 Purchasing ................................................................................................................................ 19
7.5 Production and service provision ............................................................................................... 20
7.6 Control of monitoring and measuring equipment........................................................................ 23

8 Measurement, analysis and improvement ........................................................................................ 23

8.1 General ..................................................................................................................................... 23
8.2 Monitoring and measurement .................................................................................................... 23
8.3 Control of nonconforming product.............................................................................................. 27
8.4 Analysis of data......................................................................................................................... 29
8.5 Improvement ............................................................................................................................. 29

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Foreword
2

The purpose of NSF/IPEC/ANSI 363 is to serve as an evaluation tool for analyzing pharmaceutical
excipients. Certification to this Standard serves as a communication tool between manufacturers of
excipients and finished product, pharmaceutical regulators, pharmacy organizations, and consumers.
This Standard provides guidance to allow for the determination that a pharmaceutical excipient is within
the specifications stated by the manufacturer, either qualitatively or quantitatively, and that it does not
contain specific undeclared contaminants. In some instances, validated laboratory methods are not yet
available for analyzing certain ingredients. In such cases, new methods will be added to this Standard as
they become available.

NSF/IPEC/ANSI 363 was developed with participation from the pharmaceutical excipients manufacturers,
public health regulators, and distributors of pharmaceutical excipients.

Suggestions for improvement of this Standard are welcome. This Standard is maintained on a Continuous
Maintenance schedule and can be opened for comment at any time. Comments should be sent to Chair,
Joint Committee on Pharmaceutical Excipients at [email protected], or c/o NSF International, Standards
Department, P.O. Box 130140, Ann Arbor, Michigan 48113-0140, USA.

NOT FOR
DISTRIBUTION
OR SALE

2
The information contained in this Foreword is not part of this American National Standard (ANS) and has not been
processed in accordance with ANSI’s requirements for an ANS. Therefore, this Foreword may contain material that
has not been subjected to public review or a consensus process. In addition, it does not contain requirements
necessary for conformance to the Standard.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

NSF/IPEC/ANSI Standard
for Pharmaceutical Excipients –

Good Manufacturing Practices (GMP)

for Pharmaceutical Excipients

1 General
1.1 Introduction

The principles outlined in this Standard provide a comprehensive basis for the quality management
system used in the manufacture of pharmaceutical excipients. Implementation of these principles shall
result in the achievement of three main objectives:

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a) achieve excipient realization – the organization shall implement and maintain a system that
delivers excipients with the quality attributes necessary to meet the requirements and expectations of
customers, pharmaceutical users, and regulatory authorities;

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b) establish and maintain a state of control – the organization shall ensure the manufacture and
supply of excipients is in accordance with this Standard, thus providing customers with some
assurance of continued suitability and reliability of supply; and

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c) facilitate continual improvement – the organization shall collect objective evidence to continually
develop and enhance the application of these quality management system principles to further assure
excipient consistency.

1.2 Scope

This Standard is intended to define Good Manufacturing Practices (GMP) for excipient manufacture and
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distribution for use in drug products. It sets minimum requirements for GMP applicable to all
commercially available excipients.

This Standard includes the minimum requirements of a quality management system for excipient
manufacture drawing on principles of GMP and quality systems from other relevant standards such as
those referenced in section 2.2.

NOTE 1 – The requirements of this Standard may not be sufficient for all applications of excipients. It is the
user's responsibility to determine whether or not this Standard meets the requirements for their intended
use.

NOTE 2 – Auditing excipient manufacturers ensures conformance to this Standard. This Standard is also
rd
intended to be used by duly accredited or otherwise suitably qualified 3 parties.
rd
NOTE 3 – Each user of a 3 party auditing service should make its own determination as to the
rd
qualifications of the 3 party and the applicability of the report and/or certificate issued in satisfying its
requirements, including those pertaining to its intended use of the excipient.

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GMP applies to distribution per the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 501(a)(2)(B).

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

1.3 Purpose

Excipients impact the appearance, stability, and delivery of drug products and are essential to the safety,
quality, and efficacy of these products. It is not possible to assure the consistent quality of excipients by
testing alone. Adherence to excipient Good Manufacturing Practices provides assurance that excipients
are suitable for use in drug products. Excipient Good Manufacturing Practices require a proper quality
management system, methods, facilities and controls, including appropriate tests.

2 Reference documents
2.1 Normative references

The following documents contain provisions that, through reference in this text, constitute provisions of
this Standard. At the time this Standard was written, the editions indicated were valid. All documents are
subject to revision, and parties are encouraged to investigate the possibility of applying the most recent
edition of the document indicated below. The most recent published edition of the document shall be used
for undated references.
th 4
WHO, Guidelines for Drinking-Water Quality, 4 edition, 2011

NOT FOR
2.2 Informational references

The following documents are references that provide supplemental information to the provisions of this
Standard. At the time this Standard was written, the editions indicated were valid. All documents are

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subject to revision, and parties are encouraged to investigate the possibility of applying the most recent
edition of the document indicated below. The most recent published edition of the document shall be used
for undated references.

EXCiPACT™, Certification Standards for Pharmaceutical Excipient Suppliers: Good Manufacturing

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Practices, Good Distribution Practices, 2012

FDA, Guidance for Industry: Investigating Out-of-Specification Test Results for Pharmaceutical
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Production, October, 2006
6
FDA, Guidance for Industry: Q10 Pharmaceutical Quality System, April 2009

ICH Harmonised Tripartite Guideline, Q6A: Specifications: Test Procedures and Acceptance Criteria for
7
New Drug Substances and New Drug Products: Chemical Substances, November 1999
7
ICH Harmonised Tripartite Guideline, Q8: Pharmaceutical Development, November 2005

ICH Harmonised Tripartite Guideline, Q9: Quality Risk Management, November 20057

4
World Health Organization, 1211 Geneva 27, Switzerland
<www.who.int/water_sanitation_health/dwq/guidelines/en/index.htm>.
5
EXCiPACT Association c/o, La Federation du Council International des Excipients Pharmaceutiques (IPEC
Federation), Avenue de Gaulois, 9 Brussels B-1040 Belgium < http://www.excipact.org/>.
6
Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA <www.fda.gov>.
7
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH), 15, chemin Louis-Dunant, P.O. Box 195, 1211 Geneva 20, Switzerland <www.ich.org>.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

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ISO 9001:2008, Quality management systems – Requirements, October 2008

International Pharmaceutical Excipients Council, IPEC Americas® Certificate of Analysis Guide for Bulk
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Pharmaceutical Excipients, 2013

International Pharmaceutical Excipients Council, IPEC Good Distribution Practices Guide for
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Pharmaceutical Excipients, 2006

International Pharmaceutical Excipients Council, IPEC Excipient Stability Program Guide, 20109

International Pharmaceutical Excipients Council, Joint IPEC – PQG Good Manufacturing Practices Guide
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for Pharmaceutical Excipients, 2006

The IPEC-Americas® Significant Change Guide for Bulk Pharmaceutical Excipients, Second Revision,
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March 2009

The United States Pharmacopeial Convention, United States Pharmacopeia-National Formulary (USP-
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NF), 2011

U.S. Food and Drug Administration, Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C.
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501(a)(2)(B)

3 Definitions
NOT FOR
Terms used in this Standard, which have a specific technical meaning, are defined here.

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3.1 active pharmaceutical ingredient (API): Any substance or mixture of substances intended to be
used in the manufacture of a drug product and that, when used in the production of a drug, becomes an
active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the

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structure, or any function of the body of man or animals.

3.2 adequate: Sufficient, although not necessarily the most or the best.

3.3 appropriate: A quality of being suitable for assuring conformance to the requirements.

3.4 archival system: System used to preserve information considered valuable, using media suitable for
storage and retrieval.

3.5 batch: A specific quantity of material produced in a process or a series of processes so that it may be
expected to be uniform in character and quality, within specified limits. In the case of a continuous
process, a batch may correspond to a defined fraction of the production. The batch size may be defined
by a fixed quantity or by the amount produced in a fixed time interval.

3.6 calibration: The demonstration that a particular instrument or measuring device produces results
within specified limits by comparison with results produced by using a reference or traceable standard,

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International Organization for Standardization (ISO), 1, ch. de la Voie-Creuse, Case postale 56, CH-1211 Geneva
20, Switzerland <www.iso.org>.
9
International Pharmaceutical Excipients Council of the Americas, 1655 North Fort Myer Drive, Suite 700
Arlington, VA 22209, USA <www.ipecamericas.org>.
10
The United States Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, Maryland 20852–1790, USA
<www.usp.org>.
11
US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002 <www.fda.gov>.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

over an appropriate range of measurements.

3.7 certificate of analysis (COA): A document listing the test methods, specifications, and results of
testing a representative sample from the batch to be delivered.

3.8 certificate of conformity (COC): A document that confirms the product shipped to the customer
complies with a specific set of requirements or specifications. It does not contain actual test results.

3.9 change control: A process used for management review of proposed changes that may impact the
quality or regulatory conformance of the excipient.

3.10 competency: The demonstrated personal attributes and ability to apply knowledge and skills.

3.11 component: Any material present in the excipient that arises as a consequence of the raw
materials and/or manufacturing process.

3.12 computer system: A group of hardware components and associated software designed and
assembled to perform a specific function or group of functions.

3.13 contaminant: An undesired material of a chemical or microbiological nature, or foreign matter

introduced from a raw material, intermediate, or excipient during production, sampling, packaging,
storage or transport.

3.14
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contamination: The undesired introduction of impurities of a chemical or microbiological nature,
or foreign matter into or onto a raw material, intermediate or excipient during production, sampling,
packaging or repackaging, storage, or transport.

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3.15 continual improvement: Recurring activity to increase the ability to fulfill requirements.

3.16 continuous process: A process that continually produces material from a continuing supply of
raw material.

3.17
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corrective action: The action taken to eliminate the cause of a detected non-conformity or other
undesirable situation.

NOTE − Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent
occurrence.

3.18 customer: The organization receiving the excipient once it has left the control of the excipient
manufacturer.

3.19 documented procedure: A written procedure meeting the requirements of 4.2.3.

3.20 drug product: Dosage form intended for use by a patient.

3.21 effectiveness: An expression of the degree to which activities have produced the effects
planned.

3.22 excipient: Substances other than the API that have been appropriately evaluated for safety and
are intentionally included in a drug delivery system.

3.23 excipient realization: Achievement of an excipient with the quality attributes appropriate to meet
the needs of internal customers, pharmaceutical users, regulatory authorities, health care professionals,
and patients.

3.24 expiry (expiration) date: The date designating the time before which the excipient is expected to

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

remain within specifications and after which it must not be used.

3.25 functionality: A desirable property of an excipient that aids and/or improves the manufacture,
quality, or performance of the drug product.

3.26 good manufacturing practices (GMP): Minimum requirements for the quality management
system, methods to be used in, and the facilities or controls to be used for the manufacture, processing,
testing, packing, or holding of a drug product and its ingredients. Conformance to these minimum
requirements, in part, assures that a drug (i.e., excipient, API, and drug products) will consistently meet
quality standards and assure patient safety.

3.27 ICH: International Conference on Harmonisation of Technical Requirements for Registration of

Pharmaceuticals for Human Use.

3.28 IPEC: International Pharmaceutical Excipients Council.

3.29 IPEC-PQG: International Pharmaceutical Excipients Council and the Pharmaceutical Quality
Group.

3.30 impurity: An undesirable component of an excipient that is present as a consequence of the raw
materials, excipient manufacturing process, or excipient degradation. Impurities are expected to be
controlled at a specified level.

3.31

3.32 NOT FOR

justified: A documented explanation.

label: The display of written, printed or graphic matter on the Immediate container of the excipient

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(inactive ingredient) product.

3.33 labeling: All written, printed or graphic matter accompanying an excipient at any time while it is
in-transit to the customer or being held for sale after shipment or delivery to the customer.

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3.34 lot: A batch or a specific identified portion of a batch (see “batch”).

3.35 manufacture: Various operations, such as processing, packaging, labeling, and testing.

3.36 mother liquor: The residual liquid that remains after crystallization or isolation processes.

3.37 nonconformance: A non-fulfillment of a requirement.

3.38 packaging material: A material intended to protect an intermediate or excipient during storage
and transport.

3.39 preventive action: The action taken to eliminate the cause of a potential non-conformity or other
undesirable potential situation.

NOTE − Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent
recurrence.

3.40 primary reference standard: A substance that has been shown by an extensive set of analytical
tests to be authentic material that is of high purity and to which all like standards are traced and qualified
or certified. This standard is preferably obtained from an officially recognized source. If no official
recognized source is available, the reference standard selected shall be appropriately characterized.

3.41 process: The combination of operating steps including synthesis, isolation, purification,
packaging, etc. that produces the finished excipient.

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3.42 product lifecycle: All phases in the life of the product from the initial development through
marketing until the product’s discontinuation.

3.43 production: Operations involved in the preparation of an excipient from receipt of materials
operations through processing and packaging to the finished excipient.

3.44 quality: The suitability of an excipient for its intended use as indicated by relevant physical,
chemical, and microbiological properties and as assured by compliance with this Standard.

3.45 quality control (QC): Checking or testing that specifications are met.

3.46 quality management system (QMS): A management system that directs and controls how the
organization implements quality policies and achieves quality objectives.

NOTE − Requirements for quality management systems can be found in ISO 9001 and ICH Q10.

3.47 quality risk management: A systematic process for the assessment, control, communication,
and review of risks to the quality of the excipient across its lifecycle.

3.48 quality system: See “quality management system.”

3.49 quality unit: An organizational unit independent of the production unit that fulfills both Quality

NOT FOR
Assurance (QA) and Quality Control (QC) responsibilities. This may be in the form of separate QA and
QC units, a single individual, or a single group, depending upon the size and structure of the organization.

3.50 quarantine: The status of materials isolated physically or by other effective means pending a

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decision on their subsequent approval or rejection.

3.51 raw material: A general term used to denote starting materials, reagents, and solvents intended
for use in the production of intermediates or excipients.

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3.52 record: A document stating results achieved and/or providing evidence of activities performed.
The medium may be paper, magnetic, electronic or optical, photographic, etc. or a combination thereof.

3.53 representative sample: A quantity of the excipient taken according to a prescribed rationale so
as to accurately portray the material being sampled (e.g., a batch).

3.54 reprocessing: Repetition of an activity that is a normal part of the manufacturing process and
that has been documented previously.

3.55 requirements: The explicit or implicit needs or expectations of the governing Standards.

3.56 retained sample: A representative sample of a batch/delivery that is of sufficient quantity to

perform at least two full quality control analyses and will be kept for a defined period of time.

3.57 retest date: The date when a specific batch of material must be re-examined to ensure that it is
still suitable for use.

3.58 retest/re-evaluation interval: The duration, normally expressed in months or years, from the
date of manufacture, throughout which the excipient is expected to continue to conform to the
specifications and after which must be tested to confirm it continues to meet the specifications.

3.59 retest interval: (see "retest/re-evaluation interval”)

3.60 reworking: Subjecting previously processed material that did not conform to Standards or
specifications to processing steps that differ from the normal process.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

3.61 risk analysis: The estimation of the risk(s) associated with the identified hazard(s).

3.62 risk assessment: A systematic process of organizing information to support a risk decision to be
made within a risk management process. It consists of the identification of hazards and the analysis and
evaluation of risks associated with exposure to those hazards.

3.63 secondary reference standard: A substance of established quality and purity, as shown by
comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.

3.64 shelf life: The length of time during which the excipient meets specifications (see 3.24 expiry
(expiration) date; 3.58 retest/re-evaluation internal; 3.59 retest interval).

3.65 significant change: Any change that has the potential to alter an excipient’s physical, chemical,
or microbiological property from the norm, and/or that may alter the excipient’s performance in the dosage
form.

3.66 solvent: An inorganic or organic liquid used as a vehicle for the presentation of solutions or
suspensions in the manufacture of an excipient.

3.67 specification: A test or list of tests, references to analytical procedures and appropriate
acceptance criteria that are numerical limits, ranges or other criteria that a material is required to meet.

3.68
NOT FOR
specificity: The ability to assess unequivocally the analyte in the presence of components that
may be expected to be present. Typically these might include impurities, degradants, matrix, etc.

3.69 stability: The continued conformance of the excipient to its specifications.

3.70
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state of control: A condition in which the set of controls consistently provides assurance of
continued process performance and product quality.

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3.71 subcontractor: A third party for outsourced work or services that contribute in whole or in part to
the manufacture of excipients.

3.72 top management: A person or group of people who direct and control an organization at the
highest level. The highest level may either be at the site or corporate level and will depend on how the
quality management system is organized.

3.73 traceability: The ability to determine the history, application, or location that is under
consideration (for example, origin of materials and parts, processing history, or distribution of the product
after delivery).

3.74 validation: A documented program that provides a high degree of assurance that a specific
product, method, procedure (e.g., cleaning), or system will consistently produce a result meeting
predetermined acceptance criteria.

3.75 verification: The application of methods, procedures, tests, and other evaluations, in addition to
monitoring, to determine compliance with GMP principles.

4 Quality management system

4.1 General requirements

The organization shall document, manage, and implement the quality management systems and GMP
required to assure excipient quality.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

NOTE − The elements of the quality management should be applied in a manner that is appropriate and
proportionate to each of the product lifecycle stages, recognizing the different goals and knowledge
available at each stage.

The organization shall maintain and continually improve the quality management system and GMP in
accordance with the requirements of this Standard.

4.1.1 General quality management systems organization

In defining the quality management processes the organization shall:

a) define individual and collective roles, responsibilities, authorities and inter-relationships of all
organizational units related to the excipient quality management system; ensure these interactions
are communicated and understood at all relevant levels of the organization (see 5.5.1);

b) define the interactions of the processes stated herein, with the operations needed for the quality
management system and the implementation of GMP;

NOTE − An independent quality unit with authority to fulfill certain excipient quality system
responsibilities may be required by regional regulations.

NOT FOR
c) determine the criteria and methods to ensure that the operation and control of these processes
and GMP are effective;

d) ensure that there are suitable resources, including availability of information, to support the
operation and measurement of these processes;

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e) monitor, and, where applicable, measure and analyze these processes and procedures to gain
knowledge and understanding of them; and

NOTE − Processes here include the quality management system and the manufacturing and delivery

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operations.

f) apply actions based on the science and knowledge gained to improve these processes and the
quality management system while maintaining consistent excipient quality.

NOTE − Quality risk management may be useful for identifying and prioritizing areas for continual
12
improvement.

4.1.2 Outsourcing general requirements

Where manufacturing, testing, or other operations that may affect excipient quality are outsourced, the
organization shall:

a) define the responsibility for quality and the control measures within the quality management
system (see 7.4); and

b) demonstrate that the applicable GMP principles in accordance with this Standard are applied to
those operations.

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ICH Harmonised Tripartite Guideline, Q9: Quality Risk Management, November 20055

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

4.2 Documentation requirements

4.2.1 General

The design, organization, and documentation of the quality system shall be structured to facilitate
common understanding and consistent application.

The use of appropriate quality risk management principles shall be incorporated into changes to the
quality management system.

NOTE – Quality risk management may be a useful aid to identifying activities, operations, and processes
that pose a risk to consistent physical, chemical, and/or microbiological excipient quality.

The following documents shall be included in the quality management system:

a) Quality Manual, (see 4.2.2);

b) Quality Objectives;

c) documents and records required by this Standard and any other documents necessary for the
effective planning, operation and control of the processes; and

NOT FOR
d) a documented risk assessment that defines and justifies when the as/if/where applicable clauses
in this Standard are not implemented.

NOTE 1 − A single document may address the requirements of one or more procedures. More than one
document may be used to meet the requirement for a documented procedure.

4.2.2
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NOTE 2 − The documentation may be in any form or type suitable for long-term storage and retrieval.

Quality manual

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The organization shall prepare a Quality Manual describing the quality management system, the Quality
Policy, and the commitment of the organization to apply the GMP and quality management requirements
contained in this Standard. The Quality Manual shall also include:

a) the scope of the quality management system;

b) reference(s) to supporting procedures;
c) a description of the interaction between quality management processes; and
d) justification of the processing step from which point this Standard shall be applied.

4.2.3 Control of documents

Documents required by this Standard and those determined by the organization as necessary to
implement GMP and the quality management system shall be controlled. Records are a special type of
document and shall be controlled according to the requirements specified in 4.2.4.

A documented procedure shall be established to define the controls needed to:

a) approve documents for adequacy by designated personnel prior to issue;

b) periodically review, update as necessary, and re-approve documents;

c) ensure that changes and the current revision status of documents are identified;

d) ensure that current versions of applicable documents are available at points of use;

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

e) ensure that documents remain legible and readily identifiable;

f) ensure that documents of external origin are identified and their distribution controlled; and

g) prevent the unintended use of obsolete documents and to apply suitable identification to them if
they are retained for any purpose.

Procedures that impact excipient quality shall have a defined owner and be reviewed and approved by
the quality unit before issue including changes to these documents (see 5.5.1).

Electronic documentation shall meet the requirements for the document control system stated above. If
electronic signatures are used on documents they shall be controlled to provide equivalent security to that
given by a hand written signature.

NOTE − Electronic documents and signatures may also need to satisfy local regulatory requirements.

4.2.4 Control of records

The organization shall establish and maintain a documented procedure for the identification, collection,
indexing, filing, storage, maintenance, protection, retention time, and disposition of records.

NOT FOR
Records shall be established and maintained to demonstrate achievement of the defined specifications
and conformance with this Standard. Records shall be legible and stored in such a manner that they are
readily retrievable. Electronic records shall be subjected to the same stringency of controls as those
required for other records. Pertinent subcontractor quality data shall be an element of these records.

DISTRIBUTION
Entries in records shall be clear, permanent, made directly after performing the activity (in the order
performed), signed or attributed to an individual (for electronic records), and dated by the person making
the entry. Corrections to entries shall be signed and dated, leaving the original entry legible.

OR SALE
The record retention period shall not be less than one year past the excipient’s expiry or two years past
the retest date. If the manufacturer does not stipulate an expiry or retest/re-evaluation interval, the record
retention period shall be a minimum of five years from the date of manufacture. Documented procedures
shall be implemented to ensure control of COAs.

4.3 Change control

Top management shall establish and maintain a robust change control program under the quality
management system. This program shall be designed to ensure that excipient quality is assessed and
maintained in accord with principles of quality risk management when changes are planned and
implemented, respectively.

There shall be a documented procedure for the evaluation and approval of changes that may impact upon
the quality of the excipient, including the impact on any regulatory submissions by the excipient
manufacturer. The organization shall define the criteria for a significant change (see 3.65). The evaluation
and approval of planned changes shall occur prior to the implementation of the changes. For
requirements regarding the evaluation and approval of unplanned changes, the changes should be
investigated and appropriate corrective action implemented, see 8.5.2. Upon implementation, the
effectiveness of a change shall be confirmed. The quality unit shall approve any changes that based on
risk assessment may impact the quality of the excipient. There shall be a written procedure for
determining which changes to communicate to customers, as well as a mechanism for communicating
changes. Significant changes shall be communicated with sufficient notice prior to implementation as is
reasonably practical to customers (see 7.2.3) and, as applicable, regulatory authorities. The customer
shall be informed prior to the first shipment of the excipient after the change is implemented.
Documentation generated for change control shall be retained (see 4.2.4).

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NOTE − Quality risk management may be utilized to evaluate proposed changes.

5 Management responsibility
5.1 Management commitment

Top management shall have the responsibility to:

a) ensure an effective excipient quality management system is in place to achieve the Quality
Objectives;

b) ensure that roles, responsibilities, and authorities are defined, communicated, and implemented;

c) ensure the availability of resources;

d) communicate to the organization the importance of conforming to the Quality Policy and support
achievement of the Quality and GMP Objectives;

e) provide evidence of its commitment to meeting and monitoring ongoing conformance to the
requirements of this Standard, the relevant statutory and regulatory requirements, and customer

NOT FOR
expectations;

f) ensure a timely and effective communication and escalation process exists to raise issues of
conformance to this Standard that may impact the quality of the finished excipients or changes to

DISTRIBUTION
regulatory requirements to top management (see 5.5.3); and

g) ensure management reviews are conducted on a regular basis.

NOTE − Top management has overall responsibility for the quality management system; however,

OR SALE
some tasks may be delegated to others.

5.2 Customer focus

It is the responsibility of top management to ensure customer key requirements are identified, established
and met.

NOTE – Customer key requirements as they relate to this Standard include suitable facilities, competent and
trained personnel, and operations designed to promote excipient integrity, avoidance of cross-
contamination, consistent excipient composition, and the ability to produce excipient conforming to the
customer specifications.

5.3 Quality policy

Top management shall establish a quality policy that describes the overall intentions and direction of the
organization related to quality. The Quality Policy shall:

a) include commitments to implementation of GMP, compliance with applicable regulatory

requirements, and continual improvement;

b) be communicated to and understood by personnel at all levels in the organization; and

c) be reviewed at a defined frequency for continuing suitability (see 5.6).

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5.4 Planning

5.4.1 Quality objectives

Top management shall ensure Quality Objectives are established for relevant functions and levels within
the organization for adherence to this Standard. The organization shall maintain, regularly review, and
demonstrate its performance against Quality Objectives. Quality Objectives shall be deployed throughout
the organization and shall be understood, measurable, and consistent with the Quality Policy.

5.4.2 Quality management system planning

Top management shall provide adequate resources to ensure conformance to the provisions of this
Standard.

5.5 Responsibility, authority, and communication

5.5.1 Responsibility and authority

Responsibility and authority shall be clearly defined by top management, documented, and
communicated within the organization.

A quality unit independent from production shall be responsible for conformance of the manufacture of the

NOT FOR
excipients with the requirements of this standard, including but not limited to:

a) approving and assessing the ongoing qualified status of suppliers of materials, components and
services that may impact the quality of the finished excipient;

DISTRIBUTION
b) approving or rejecting raw materials, packaging components, intermediates and finished
excipients;

c) ensuring production records are reviewed to confirm that the process remains in a state of control

OR SALE
throughout, and to identify discrepancies including errors in operation that require investigation;

d) approving the documented results of investigations into manufacturing deviations or

discrepancies, test or measurement errors and failures, and complaints;

e) ensuring corrective and preventive actions are implemented;

f) reviewing proposed changes that have the potential to impact excipient quality (see 4.3);

g) approving changes that have the potential to impact excipient quality prior to implementation (see
4.3);

h) approving or rejecting the excipient if it is manufactured, processed, packaged, or held under

contract by another company;

i) developing and implementing an internal audit program; and

j) ensuring that providers of outsourced services have agreed to comply with the relevant sections
of the Standard.

The Quality Unit may delegate some aspects of these activities if justified as appropriate, however, they
shall retain ultimate responsibility for oversight and approval of all delegated activities, applicable
controls, and final decisions.

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An organization chart by function shall show inter-departmental relationships as well as relationships to

top management of the organization.

5.5.2 Management representative

A member of the organization’s management shall be appointed and given authority by top management
to ensure the provisions of this Standard are properly implemented. The management representative
shall have demonstrated qualifications and experience. The management representative shall hold a
senior position in the quality unit unless otherwise justified.

5.5.3 Internal communication

The organization shall ensure appropriate systems are established to communicate throughout the
organization the requirements of this Standard and applicable regulatory requirements. The
communication shall also provide information about the effectiveness of the excipient quality
management system.

Based on risk assessment, top management shall be notified in a timely manner of events that affect
excipient quality and shall support appropriate corrective and preventive actions, in accordance with a
documented procedure.

5.6 Management review

5.6.1 General
NOT FOR
Top management shall hold scheduled reviews of the excipient quality management system to confirm

DISTRIBUTION
continued conformance to this Standard. These reviews shall be documented. Any opportunities for
improvement shall be assessed and implemented via the change control procedure (see 4.3).

NOTE − For excipient quality review requirements, see 8.2.3.

OR SALE
5.6.2 Review input

The management review inputs shall include, at a minimum, performance metrics and trends for:

a) action items from the previous management review;

b) results of internal and external audits;
c) excipient conformity and process performance;
d) customer feedback regarding the organization’s performance;
e) customer complaints;
f) status and review of corrective and preventive actions;
g) changes to the excipient quality management system;
h) new, revised, and proposed compendial and regulatory requirements; and
i) recommendations for excipient quality management system improvement.

5.6.3 Review output

The management review shall identify the resources needed and opportunities presented for
improvement of the quality management system and improvement of excipient conformance to customer
and regulatory requirements. A record shall be made of all actions ordered and taken.

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6 Resource management
6.1 Provision of resources

The organization shall provide sufficient resources and qualified personnel to implement and continually
improve the excipient quality management system and to manufacture, package, test, store, and release
each excipient batch in a manner consistent with this Standard.

NOTE – A gap analysis based on audits by internal personnel, customers, regulatory agencies, or outside
contractors to this Standard may be used for the purpose of identifying resource requirements.

6.2 Human resources

6.2.1 General

Personnel who have a direct or significant impact on excipient quality shall have job descriptions and
defined responsibility and authority. Personnel performing and supervising work with the potential to
affect the quality of excipients shall have the appropriate combination of education, training, and
experience to perform their assigned tasks.

Consultants advising on the design, production, packaging, testing, or storage of excipients shall have the
education, training, and experience or any combination thereof that qualifies them to advise on the

NOT FOR
subject for which they are retained. The organization shall maintain records listing the name, address,
and qualifications of consultants and the type of service they provide.

6.2.2 Competence, awareness, and training

DISTRIBUTION
The organization shall identify, establish, and document the training needs for personnel having the
potential to affect excipient quality or elements of this Standard. These employees including their
supervisors shall be adequately trained prior to carrying out their assigned duties. Training shall include,
at a minimum:

OR SALE
a) the particular operations the employee performs;

b) the elements of this Standard as they relate to the employee’s duties;

c) the elements of hygienic practices for personnel whose activities or responsibilities have the
potential to result in contamination of the excipient including an explanation of how these are a
hazard to the end user/patient;

d) the reporting of significant failures and deviations from procedures including the impact deviations
from procedures may have on excipient quality; and

e) the importance of consistent adherence to good manufacturing practice, and their role in assuring
drug product performance and patient safety.

The training shall be delivered by qualified individuals at sufficient frequency to ensure employees remain
familiar with current procedures and applicable elements of this Standard. The organization shall maintain
records of training, including content, attendance, and trainer qualifications.

6.2.3 Hygienic practices

To protect excipients from contamination, the organization shall conduct a risk assessment to identify
areas where the excipient is at risk of contamination from personnel and/or their activities. The following
shall be considered at a minimum to protect the excipient from contamination:

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a) the personnel, including their hygiene, any apparent illness or open lesions, and their attire;
b) the equipment used by the personnel;
c) the opportunity for loose items to fall into the excipient;
d) the access of unauthorized personnel to designated areas; and
e) the storage and use of food, drink, personal medication, tobacco products, or similar items.

Suitable control measures shall be implemented to mitigate the identified risks.

Personnel shall be instructed to report to supervisory personnel any health conditions that may have an
adverse effect on excipients.

6.3 Infrastructure

The infrastructure shall be operated, cleaned, and maintained in accordance with this Standard to ensure
excipient quality and the avoidance of contamination or mix-ups.

6.3.1 Buildings and facilities

Contamination prevention shall be considered in the design, maintenance, refurbishing, or upgrading of

buildings and facilities.

The organization shall conduct a risk assessment based on the organization’s expressed, intended use of

NOT FOR
the excipient (see 7.2.3) to identify areas in which the excipient is at risk of contamination, cross-
contamination, or mix-ups due to deficiencies in buildings and/or facilities. The risk assessment shall
consider the following, at a minimum, to identify where the excipient is at risk of contamination:

DISTRIBUTION
a) state of repair of the building and facility;
b) suitable size, construction, and location;

NOTE − Where equipment is located outdoors there shall be suitable control to minimize the risk to
excipient quality from the environment, including seasonal variations.

OR SALE
c) ability to maintain a suitably clean building and facility environment;
d) operations inside or outside of the building or facility that may affect the excipient quality; and
e) presence of environmental contaminants, including microorganisms.

Suitable control measures shall be implemented to mitigate the identified risks. Access to areas of the
buildings and facilities designated as limited access areas shall be controlled.

6.3.2 Equipment

Equipment used in the production, processing, packaging, testing, or storage of an excipient shall be:

a) maintained in a good state of repair;

b) of suitable size, construction, and location to facilitate cleaning, maintenance, and correct
operation, commensurate with the type of processing;

c) constructed so contact surfaces will not be reactive, additive, or absorptive;

d) designed, installed and stored when disconnected so as to assure proper sanitary condition
including appropriate provisions for drainage; and

e) equipment such as change parts, utensils and hoses shall be cleaned and stored in such a way
as to render them fit for use in the manufacture of excipients.

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Design deficiencies that may impact excipient quality shall be addressed with mitigation strategies.

6.3.2.1 Equipment construction

New installations or replacement equipment shall be designed to minimize the possibility of contamination
and shall be commissioned before use to ensure it is functioning as intended.

The risk of contamination from utilities and process materials (i.e., compressed gases, steam, water) or
other media used for proper equipment operation (lubricants and heat transfer fluids) coming into contact
with raw materials, packaging materials, intermediates, or finished excipients shall be identified. When
risks are identified, they shall be mitigated so as to minimize the possibility of contact with the process
stream. Where contact is possible, materials suitable for food contact are preferred. The use of materials
not suitable for food contact should be justified.

6.3.2.2 Equipment maintenance

Procedures and associated schedules unless otherwise justified based on a documented risk
assessment, shall be established for the maintenance of equipment used in the production, processing,
packaging, testing, and holding of the excipient. Deviations from the normal maintenance schedule shall
be justified.

There shall be chronological records of the use, maintenance, and associated cleaning of equipment

NOT FOR
coming into contact with the process stream. There shall be a standard procedure for the storage of
equipment not in use.

6.3.2.3 Computer systems

DISTRIBUTION
The organization shall document the following for computer systems that impact excipient quality:

a) consistent operation of the system;

OR SALE
b) prevention of unauthorized access;

c) assessment of equipment or automated systems used in production and control;

d) disaster recovery procedures, including retention of suitable back-up or archival systems;

e) maintenance and assurance that changes are verified and documented and only made by
authorized personnel; and

f) provisions to assure the maintenance of data and data integrity.

6.3.3 Utilities

The organization shall conduct a risk assessment considering the risk to excipient quality from utilities
intended to, and with the potential to come into contact with the excipient (e.g., utilities can include
nitrogen, compressed air, steam, water, etc.). Control measures shall be implemented to mitigate the
identified risks. Utilities coming into direct contact with the excipient during its manufacture or surfaces
that could contact excipients shall have documented specifications to assure that the utility is suitable for
its intended use.

6.3.4 Water

Unless otherwise justified, water shall, at a minimum, meet the WHO Guidelines for Drinking-Water
Quality, be distributed in a well-designed sanitary system, and be provided either under continuous
positive pressure or with other robust means of preventing back flow. Water quality limits, shall be

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consistent with the desired excipient quality standards. The water purification system and process shall
be specified, and the quality of the water monitored and controlled within appropriate microbiological and
chemical limits based on intended use of the excipient. Where there is water available of multiple
qualities, provision shall be made to avoid mix-up.

If interruptions to supply or deviations in the quality of such water occur, evidence and appropriate
rationale shall be documented to show such deviations or interruptions have not compromised the quality
of the excipient. Production shall not recommence until it has been shown that the water has returned to
its designated quality.

6.4 Work environment

The organization shall conduct a risk assessment to identify areas in which the excipient is at risk for
contamination from exposure to the work environment.

The work environment shall be managed and controlled to minimize risks of excipient contamination.

The documented risk assessment shall include customer requirements (see 7.2.2), marketed use, and, as
applicable, shall consider the following controls:

a) air handling systems;

b) special environments;

NOT FOR
c) cleanliness and sanitary conditions;
d) waste segregation and disposal;
e) pest control; and
f) other risk assessments required by this Standard (see 6.2 and 6.3).

DISTRIBUTION
A documented risk assessment shall be carried out to determine the necessary controls. Controls shall be
implemented, monitored and documented.

6.4.1 Air handling

OR SALE
Where the risk assessment has identified that an air handling system poses a potential risk to excipient
quality, the air handling system shall be designed and maintained to assure adequate protection of the
excipient. The organization shall demonstrate its effectiveness.

6.4.2 Controlled environment

Where the risk assessment has identified the need for a controlled environment, it shall be monitored to
assure excipient quality.

Where an inert atmosphere is required, the gas shall be treated as a raw material as defined in 7.4.3.

If interruptions in the controlled environment occur, the organization shall perform an investigation to
document adequate evidence and appropriate rationale to show such interruptions have not
compromised the quality of the excipient.

6.4.3 Cleaning and sanitary conditions

Waste shall be segregated and disposed of in a timely and appropriate manner. If waste is not disposed
of immediately, it shall be suitably identified.

Where the risk assessment (see 6.3.1) has identified that clean and/or sanitary conditions of the work
environment are necessary to protect excipient quality, the organization shall document procedures
assigning responsibility for cleaning and/or sanitation. Cleaning and/or sanitization records shall be
maintained.

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6.4.4 Pest control

A pest control program shall be implemented. The elements of the pest control program shall be
determined by risk assessment.

6.4.5 Lighting

Adequate lighting shall be provided to facilitate cleaning, maintenance and proper operations.

Where the excipient is exposed to the work environment or stored, lighting shall be shatter-proof or
otherwise protected.

6.4.6 Drainage

In areas where the excipient is exposed to the work environment or stored, drains shall be of adequate
size. Drains connected directly to a sewer shall be provided with an air break or other mechanical device
to prevent back-siphoning.

6.4.7 Washing and toilet facilities

Personal washing facilities shall be provided, including hot and cold water, soap or detergent, and air

NOT FOR
dryers or single service towels. Clean toilet facilities shall be separate from but easily accessible to
working areas.

Based on the results of the risk assessment in 6.2.3, facilities for showering and/or changing clothes shall

DISTRIBUTION
be provided.

7 Excipient realization

OR SALE
7.1 Planning of excipient realization

The organization shall plan and develop the processes and controls needed for excipient manufacture,
including implementation of identified actions from risk assessments described in other sections of this
Standard. These plans and controls shall be appropriate to the production process, including
subcontractor activities, and include:

a) human resources, equipment, and facilities for storage and testing used in the manufacture and
supply of the excipient;

b) testing programs for materials used in the manufacture of the excipient and the finished excipient
that include appropriate specifications, sampling plans, and test and release procedures; and

c) environmental and hygiene control programs to minimize the potential for contamination of the
excipient.

The record system shall demonstrate that these processes and controls were followed.

The use of recycled or recovered materials containing recoverable amounts of excipient, reactants, or
intermediates shall be justified.

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7.2 Customer-related processes

7.2.1 Determination of requirements related to the product

The organization shall determine the excipient quality, labeling, legal, and regulatory requirements, as
well as those provided by the customer. Requirements not stated by the customer but necessary for the
specified or intended use, where known, shall be considered. Changes requiring notification and/or
documented prior approval from the customer shall be determined.

7.2.2 Review of requirements related to the product

The organization shall review the requirements identified in 7.2.1 to assure the facilities and processes
are capable of consistently meeting these requirements and shall document the review and agreement
with the customer before supply commences. Where the requirements determined in 7.2.1 are changed,
this review shall be repeated before supply recommences.

7.2.3 Customer communication

The organization shall provide accurate and pertinent communication to the customer. The organization
shall determine the types of excipient quality-related documents to be shared with customers. At a
minimum, master copies of quality-related documents made available to customers shall be controlled
within the organization. Provision shall be made for replying to mutually agreed customer requirements

NOT FOR
and contracts. Customer feedback and complaints shall be documented.

The organization shall define how potentially significant changes are assessed (see 7.2.2) and
communicated to customers (see 4.3).

DISTRIBUTION
Deviations that may impact excipient quality and which become known after delivery of the excipient shall
be evaluated and communicated to customers. The impact of such deviations shall be assessed and
provision made for return of excipient as necessary (see 8.3).

OR SALE
7.2.3.1 Customer complaints

Written procedures describing the handling of all written and oral customer complaints shall be
established and followed. Such procedures shall include provisions for recordkeeping, timely review and
investigation of complaints, and follow up activities.

7.3 Design and development (out of scope)

7.4 Purchasing

7.4.1 Purchasing process

The organization shall establish a documented system for selecting, approving, and reapproving suppliers
of materials and services. Materials and services that have the potential to impact excipient quality shall
be identified from risk assessments. Materials shall be purchased against a mutually agreed specification.

The organization’s quality unit shall undertake a risk assessment to determine materials and services that
have the potential to impact excipient quality and approve such suppliers.

For such materials and services, the supplier shall have an agreement to notify the organization of
significant changes. If an agreement cannot be obtained, a risk assessment shall be performed and a
written justification and mitigation plan for continued use of the supplier implemented.

The organization shall require that contract service providers adhere to the relevant sections of this
Standard.

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7.4.2 Purchasing information

The organization shall communicate purchasing information to approved suppliers. The purchasing
information shall describe the material or service ordered including, at a minimum, the following:

a) reference to the current agreed specification or description of service requirements; and

b) drawings, process requirements, inspection instructions, and other relevant technical data,
including requirements for approval or qualification of product, procedures, process equipment, and
personnel.

7.4.3 Verification of purchased product

The organization shall establish procedures to verify, approve, and release purchased material used for
excipient manufacture and packaging. The organization shall justify any material not sampled prior to
approval and release, such as when the material is too hazardous or toxic to sample and test. The
organization shall verify that the measurements reported on the supplier Certificate of Analysis for each
lot meet the agreed specification. For packaging components, the organization shall verify the Certificate
of Conformance references the current agreed specification. Wherever feasible, the organization shall
perform at least an identification test or otherwise confirm the identity of the material.

NOT FOR
Procedures shall describe the quarantine of purchased materials prior to their approval. Where
quarantine of unapproved material is not possible, the organization shall have an agreement with the
supplier so they are promptly notified of material that does not meet specifications.

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Any sampling activities shall be performed in accordance with a defined method for obtaining
representative samples and using procedures designed to prevent contamination and cross-
contamination.

The organization shall establish controls to assure materials delivered in bulk or returned and reused

OR SALE
containers are free from contamination and fit for its intended purpose.

7.5 Production and service provision

7.5.1 Control of production and service provision

The organization shall conduct excipient production activities in accordance with the following:

a) production instructions that describe the manufacture of the excipient and that establish records
providing sufficient detail to ensure the following:

1) the excipient was manufactured and packaged according to the production instructions;

2) documentation to demonstrate activities were performed in conformance with excipient

production requirements;

3) the identification of individuals performing such activities;

4) the traceability of materials (including recycled and recovered materials); and

5) the identification and traceability of equipment used, its maintenance, and cleaning.

b) equipment and utensil cleaning and sanitization procedures justifying the method and frequency
of cleaning, establishing criteria for determining effectiveness, and requiring chronological records of
cleaning activities as noted above; the cleaning status of equipment shall be known;

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c) state of process control using documented in-process testing;

d) packaging and labeling control procedures shall ensure that the material is traceable. Provisions
shall ensure that the containers are not mislabeled as to lot and/or product; and

e) when excipient is repackaged, the original dates of manufacture and expiry or retest period shall
be retained unless there is scientific justification otherwise.

Where solvents are recovered for reuse, they shall meet appropriate specifications prior to reuse or
mixing with other approved solvent.

7.5.2 Validation of processes for production and service provision

The organization’s excipient quality management system shall provide ongoing evidence that the
processes are capable of consistently achieving the desired quality outcome based on knowledge of
process parameters, excipient attributes, and their inter-relationship.

NOTE − The same validation program typically performed in the pharmaceutical industry may not always be
carried out by the excipient manufacturer. However, consistent operation may be demonstrated by, for
example, process capability studies, intensified monitoring and testing, development and scale-up reports,
etc.

NOT FOR
After significant changes, the impact on validation or process capability shall be assessed. Where the
intent of blending or mixing is to ensure final batch uniformity, it shall be demonstrated that such
processing achieves a state of homogeneity.

DISTRIBUTION
7.5.3 Identification and traceability

The organization shall establish a system to identify the materials used in the manufacture and packaging
of the excipient and their inspection status.

OR SALE
Records shall provide traceability of the excipient and contact packaging throughout excipient realization
to delivery to customers. Methods used for identification and traceability of raw materials used in
excipients produced by continuous processing shall be defined.

The organization shall ensure there is a process to communicate the origin and traceability of the
excipient to the customer. Labeling shall meet applicable regulatory requirements, and, at a minimum,
labeling shall include:

a) the name of the excipient and, if applicable, grade;

b) the organization’s name and identity of the manufacturing site;
c) the batch number;
d) storage conditions, if other than ambient (i.e., uncontrolled temperature and humidity); and
e) expiration date or retest date.

NOTE − These requirements can be met by codes on the label.

7.5.4 Customer property

The organization shall establish and maintain procedures for verification, storage, and maintenance of
customer-supplied materials intended for incorporation into or packaging of the customer's excipient.
Customer-supplied material that is lost, damaged, or is otherwise unsuitable for use, shall be documented
and reported to the customer. The organization shall establish a written agreement with the customer for
the acceptable disposition and replacement of lost, damaged, and/or unsuitable material.

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The organization shall also make provisions to protect other real and intellectual property (e.g., test
equipment, test methods, and specifications) provided by the customer.

7.5.5 Preservation of product

The organization shall define and justify the conditions for the handling and storage of materials (see
7.5.3) so their identity, quality, and conformance to specification are not affected within their shelf life or
retest/re-evaluation interval. Records of storage conditions shall be maintained when such conditions may
impact the material’s quality characteristics. Deviations from specified storage conditions shall be
assessed and documented.

7.5.5.1 Raw material packaging systems

Where a risk assessment has demonstrated that storage and handling of raw materials may impact
excipient quality, the organization shall:

a) provide suitable protection against deterioration, contamination with foreign substances,

chemical and/or microbiological contamination; and

b) ensure that identification labels remain legible.

7.5.5.2 Excipient packaging systems

NOT FOR
The selection of excipient packaging systems shall be justified by the organization. Excipient packaging
systems shall include the following features:

DISTRIBUTION
a) documented specifications;

b) documented evidence that the packaging does not adversely impact quality (e.g., packaging is
not reactive, additive, or absorptive);

OR SALE
c) documented cleaning procedures (where containers are reused);

d) tamper-evident seals, unless written justification demonstrates that it is not feasible; and

NOTE − A tamper-evident seal is generally feasible. The seal should have a distinct design and
possess unique identifying characteristics that are difficult to duplicate. Tamper-evident seals should be
traceable to and, where feasible, accounted for by the excipient manufacturer and should not be
reusable once the seal is broken.

e) compliance with relevant regulatory requirements.

Containers shall be stored so as to protect their cleanliness. Where reusable excipient containers are
returned, the organization shall undertake a risk assessment and establish appropriate controls for their
further use. Procedures shall ensure all previous labels are removed or completely obliterated.

7.5.5.3 Excipient delivery

Where contractually specified, protection shall extend to include delivery to the final destination. Suppliers
of transport services shall be provided with the required transport controlled conditions in order for them
to maintain required conditions.

For bulk transport in equipment not dedicated to the excipient, verified cleaning procedures shall be
applied between loadings, and a list of restricted and/or allowed previous cargoes shall be supplied to the
transport companies. Records of cleaning shall be retained.

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Excipients shall only be supplied within their expiry period, or as otherwise contractually agreed or
specified. When no expiry period is defined, the excipient shall only be supplied within its retest/re-
evaluation interval as supported by stability data (see 8.2.4.7).

Distribution records of excipient shipments to the initial customer, including identification and traceability,
shall be maintained and shall include, at a minimum:

a) excipient name or unique identifier;

b) excipient batch number;
c) type of packaging;
d) where and to whom the excipient was shipped;
e) quantity shipped; and
f) date of shipment.

7.6 Control of monitoring and measuring equipment

The organization shall use calibrated and/or verified measuring and test devices. Such measuring and
test devices shall have the appropriate specificity and sensitivity. Records of calibration and/or verification
results shall be maintained.

The organization shall establish a list of procedures for the calibration and maintenance of all measuring
and test devices, including computerized systems, unless otherwise justified. The control program shall

NOT FOR
include the standardization or calibration of measuring and test devices at suitable intervals. This program
shall contain specific limits for accuracy and precision, and provisions for remedial action in the event that
accuracy and/or precision limits are not met. Calibration and confirmation standards shall be traceable to
applicable national, international, or compendial standards. Where no such standards exist, the basis

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used for calibration or verification shall be justified.

The calibration status of equipment shall be identified and accessible to the user of the equipment.

If a measurement or test device is found out of calibration, a documented investigation shall be conducted

OR SALE
to determine the validity of results since the last calibration or documented measurement confirmation.
Appropriate action shall be taken based on the results of the investigation.

8 Measurement, analysis and improvement

8.1 General

The organization shall plan and implement the monitoring, measurement, and improvement activities
required to demonstrate conformity of the excipient to customer requirements and to ensure conformity of
the quality management system to this Standard.

The organization shall evaluate opportunities for improvements through the measurement and analysis of
product and process trends.

8.2 Monitoring and measurement

8.2.1 Customer satisfaction

The organization shall assess customer satisfaction. The assessment shall support continual
improvement.

NOTE − Such measurements may include investigation of and response to customer complaints, return of
excipients, and customer feedback.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

8.2.2 Internal audit

The organization shall carry out a comprehensive system of planned, scheduled, and documented
internal quality audits. Audits shall be conducted by qualified individuals, independent of the area being
audited, according to documented procedures that include, at a minimum, the following:

a) determination of the effectiveness of quality activities;

b) compliance with procedures and processes described by the quality management system;

c) schedules based on findings from previous audits, performance measures (see 8.2.3), and the
potential impact of the activity to finished excipient quality;

d) provisions for follow-up actions;

e) positive findings that support the effective implementation of GMP; and

f) deficiencies that need corrective and/or preventive action.

Audit results shall be documented and discussed with management personnel having responsibility in the
area(s) audited. Management personnel responsible for the area(s) audited shall take corrective action
and/or preventive action without undue delay on each nonconformance found.

8.2.3
NOT FOR
Monitoring and measurement of processes

The organization shall identify the tests and measurements necessary to adequately control the

DISTRIBUTION
manufacture and quality of the excipient.

Where there is the potential to impact excipient quality, methods used to verify that the processes are in
control shall be established and documented.

OR SALE
Regular review of key indicators, process performance, including critical process parameters and critical
quality attributes, shall be conducted to assess the need for improvements.

8.2.4 Monitoring and measurement of product

The organization shall establish, and provide documentation to support the test methods and procedures
used to verify that the excipient meets specification, and that the methods are suitable for their intended
purpose.

If the organization claims the excipient is in compliance with a pharmacopoeia or an official compendium,
then:

a) non- compendial analytical tests used as an alternative to compendial tests shall be

demonstrated to be at least equivalent to those in the compendia;

b) the excipient shall comply with applicable monographs, general chapters and notices; and

c) responsibility for monitoring those pharmacopoeia or official compendium shall be assigned.

NOTE 1 − The US Federal Food, Drug, and Cosmetic Act recognizes two official compendia: United
States Pharmacopeia (USP) and National Formulary (NF).

NOTE 2 − The USP-NF is legally comprised of two separate compendia published in the same book.

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NOTE 3 − The General Notices to both the USP and NF apply to all monographs in the respective
compendium unless otherwise stated.

NOTE 4 − In the USP-NF General Chapters having a number below <1000> are mandatory. Chapters
having a number between <1000> and <1999> are General Information Chapters. However, if a
General Information Chapter is referenced in a particular monograph, it becomes mandatory for that
monograph. (Chapters with numbers <2000> or greater apply only to nutritional supplements.)

NOTE 5 − Other pharmacopoeias have different ways of presenting such information. The introductory
notices to the specific pharmacopoeia should be consulted.

8.2.4.1 Laboratory controls and records

8.2.4.1.1 Laboratory controls

Laboratory controls shall include sufficient data derived from tests necessary to verify conformance with
specification and standards including:

a) data to enable identification and traceability of samples which are used to determine batch status;
b) record of sample preparation in conformance with test requirements;
c) traceability to the test method used;
d) a record of raw data generated during each test;
e) a record of calculations performed in connection with each test;

NOT FOR
f) test results and how they compare with established specification; and
g) a record of the person who performed each test and the date(s) the tests were performed.

8.2.4.1.2 Laboratory procedures

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There shall be documented procedures for the following:

a) laboratory reagents and test solutions prepared in-house shall include a record of their
preparation; whether prepared in-house or purchased, labeling shall include name, concentration,

OR SALE
date of first use or date of preparation, and the assigned expiration or restandardization date;

b) provisions for the receipt, storage, and use of primary reference standards; and

c) preparation, identification, testing, approval, and storage of secondary reference standards,

including qualification and the requalification period against the primary reference standard.

8.2.4.2 Finished excipient testing and release

Measures for verification of excipient quality shall be performed and recorded to confirm that the excipient
conforms to documented specification.

There shall be a procedure to ensure the quality unit has evaluated the appropriate manufacturing and
test documentation prior to quality unit release of the finished excipient.

8.2.4.3 Out-of-specification test results

Where the finished material is tested to confirm it is suitable for sale as an excipient, and the result
indicates it is non-conforming, the organization shall conduct a thorough investigation of all out of
13
specification (OOS) test results , starting with a prompt laboratory investigation, according to a
documented procedure. The findings of the investigation, including conclusions and follow
up actions, shall be recorded.

13
FDA Guidance for Industry: Investigating Out-of-Specification (OOS)Test Results for Pharmaceutical Production,
October 2006.

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

The OOS procedure shall provide detailed steps for conducting an investigation. The procedure shall
define appropriate provisions for investigation of original test results, including but not limited to:

a) criteria for retesting original sample;

b) criteria for resampling; and

c) the need to perform an investigation of manufacturing to determine the cause of the failure when
the laboratory investigation yields no conclusive assignable cause that invalidates the original result.

The results of the OOS investigation shall be used to determine batch disposition.

8.2.4.4 Retained samples

A representative sample of each batch of the excipient shall be retained unless otherwise justified and
documented. The retained sample retention period shall be justified.

Retained samples shall be stored in a secure location, readily retrievable, and under conditions consistent
with specified storage conditions.

The sample size shall be at least twice the amount required to perform complete specifications testing.

NOT FOR
8.2.4.5 Certificates of analysis

The organization shall provide Certificates of Analysis to the required specification for each batch of

DISTRIBUTION
excipient.

The Certificate of Analysis shall include, at a minimum:

a) excipient name (trade name), and, if applicable, grade, and compendial name and compendial

OR SALE
reference, or reference to the excipient specification;

b) organization’s name and identity of the site of manufacture. If the site of manufacture is not
detailed on the Certificate of Analysis then this information shall be communicated separately;

c) date of manufacture;

d) batch number;

e) expiration date or retest date, and, if previously retested, the date it was retested;

f) statement of conformance to the required specification;

g) statement of compliance to GMP as defined by this Standard (may be otherwise communicated

with the customer);
14
h) analytical results representative of the batch ; if not based on testing of a sample of the finished
excipient the basis of the results shall be communicated to the customer, (see NOTE below for
alternatives to finished excipient testing, as appropriate);

i) acceptance criteria;

14
A supplier may provide results on the CoA from a method that has been demonstrated to be either equivalent or
better than the specified method. See PQRI joint position paper on control strategies.
http://www.pqri.org/pdfs/Excipient_Position_Paper_Final_06212007.pdf

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

j) reference to the analytical method used; and

k) name and title of person whose signature appears on the Certificate of Analysis.

NOTE − See guidance as provided by the IPEC Americas® Certificate of Analysis Guide for Bulk
Pharmaceutical Excipients.

8.2.4.6 Excipient composition

Unless otherwise justified the organization shall develop an excipient composition profile and set limits to
monitor composition and control manufacturing processes so that the excipient composition is maintained
within appropriate ranges. Limits for excipient composition, including upper limits for impurities, shall be
established based on an understanding of safety considerations, regulatory requirements, official
compendia, and customer requirements.

8.2.4.7 Stability and expiry/retest periods

The stability of the excipient shall be documented.

The stated stability of the excipient shall be demonstrated through at least one of the following methods:

NOT FOR
a) historical data; or
b) stability studies.

An expiry or retest/re-evaluation interval for the excipient shall be determined, justified, and
communicated to the customer.

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NOTE − See guidance as provided by the IPEC Excipient Stability Program Guide.

8.3 Control of nonconforming product

OR SALE
Raw material, intermediate, or finished excipient not meeting its specification shall be clearly identified
and controlled to prevent inadvertent use or release for sale. Procedures shall exist for the evaluation and
appropriate disposition of nonconforming raw materials, intermediates and excipients. There shall be
procedures to prevent shipment of excipients that would be unacceptable to certain customers, when a
customer-specific requirement is not met.

For a non-conforming excipient that is already in distribution. There shall be a documented procedure
defining how the retrieval shall be conducted and recorded.

8.3.1 Investigation of non-conforming finished excipient

Failure of a batch to meet specifications for the excipient grade being produced, including failure to meet
a customer-specific requirement, shall be investigated to identify the root cause, impact on other
batches/products, and appropriate corrective and preventative actions (see 8.5).

Once the root cause is identified, corrective and/or preventative action shall be taken to bring the process
back into a state of control (see 4.3 and 8.5). A record of each incidence of non-conformance shall be
documented and maintained. The potential impact of any change on validation shall be assessed.

NOTE − In certain circumstances a particular customer may have additional specification requirements
beyond the general sales specification(s) for material manufactured using the same equipment and process
as the general material. If material manufactured in compliance with this Standard meets requirements of
the general sales specification(s) but not an individual customer specification(s) it may still be sold to those
customers for whom it does meet their specification(s).

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

8.3.2 Disposition of non-conforming finished excipient

Upon the conclusion of the investigation as described in 8.3.1, the quality unit shall assign one of the
following final dispositions to the finished excipient:

a) released as an excipient grade for which all established requirements are met;
b) reprocessed or reworked (see 8.3.3 or 8.3.4);
c) released as a non-pharmaceutical grade material; or
d) destroyed.

8.3.3 Reprocessing

Reprocessing shall only occur when it has already been documented that the excipient may be made in
the same manner. The organization shall maintain records of reprocessing activities in order to ensure
traceability of the reprocessed material into the finished excipient.

8.3.4 Reworking

Reworking is a change under the provisions of change control in this Standard (see 4.3) and shall only be
conducted following a documented review of risk to excipient quality that is approved by the quality unit.

NOT FOR
When performing the risk assessment, a documented investigation shall be completed and the following
shall be considered, unless otherwise justified:

a) additional testing to monitor and control the reworking;

DISTRIBUTION
b) additional acceptance criteria for the reworked excipient;
c) impact on stability or the validity of the retest/re-evaluation interval;
d) composition profile changes as a result of reworking;
e) performance of the excipient; and
f) need to notify the customer of reworked excipient.

OR SALE
There shall be records and traceability to the original batches. The equivalence of the quality of reworked
material to original material shall also be evaluated and documented to demonstrate the batch will
conform to established specification and characteristics. The evaluation shall be approved by the quality
unit.

When blending is used for reworking, the resultant product shall demonstrate the same chemical and
physical properties and performance characteristics as routine production.

Blending batches that are contaminated or adulterated to reduce the contamination or adulteration below
an acceptable or detectable limit is not acceptable under this Standard.

8.3.5 Returned excipients

There shall be procedure(s) for the evaluation, holding, testing, reprocessing, and reworking of returned
excipient.

Returned excipients shall be identified and controlled to prevent inadvertent use or release for sale until a
documented evaluation of their quality has been completed by the quality unit. When the intent is to make
returned excipient available for sale to another pharmaceutical customer, the evaluation shall consider
conformance to the required storage and/or transportation conditions throughout the supply chain. The
excipient shall not be released if there is any reason to believe that container integrity or excipient quality
may have been compromised.

Records for returned excipients shall be maintained and shall include the excipient name, batch number,

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© 2014 NSF NSF/IPEC/ANSI 363 – 2014

reason for return, identity of the organization that returned the excipient, quantity returned, and ultimate
disposition of the returned excipient. The quality unit shall determine and record the ultimate disposition of
returned excipient.

8.4 Analysis of data

The organization shall define methods for evaluating:

a) the effectiveness of its quality management system;

b) the ability to consistently produce conforming excipients;
c) excipient nonconformance with this Standard, customer complaints, deviations, etc.; and
d) supplier nonconformance.

The organization shall use results and trends to identify opportunities for improvement (see 5.6 and
8.5.1).

8.5 Improvement

8.5.1 Continual improvement

The organization shall periodically review, including data as described in 8.4, for opportunities to improve
manufacturing and quality management system processes.

8.5.2
NOT FOR
Corrective action

The organization shall establish procedures for:

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a) determining the root causes of nonconformance;
b) ensuring that corrective actions are implemented and effective; and
c) implementing and recording changes in procedures resulting from corrective action.

OR SALE
8.5.3 Preventive action

The organization shall establish procedures for:

a) initiating preventive actions commensurate with the corresponding risks;

b) implementing and recording changes in procedures and processes resulting from preventive
action; and

c) ensuring that preventive actions are implemented and effective.

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This page is intentionally left blank.

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 Standards
15

The following standards established and adopted by NSF as minimum voluntary consensus standards are used internationally:

2 Food equipment
3 Commercial warewashing equipment
4 Commercial cooking, rethermalization, and powered hot food holding and transport equipment
5 Water heaters, hot water supply boilers, and heat recovery equipment
6 Dispensing freezers
7 Commercial refrigerators and freezers
8 Commercial powered food preparation equipment
12 Automatic ice making equipment
13 Refuse processors and processing systems
14 Plastics piping system components and related materials
18 Manual food and beverage dispensing equipment
20 Commercial bulk milk dispensing equipment
21 Thermoplastic refuse containers
24 Plumbing system components for recreational vehicles
25 Vending machines for food and beverages
29 Detergent and chemical feeders for commercial spray-type dishwashing machines
35 High pressure decorative laminates (HPDL) for surfacing food service equipment
36 Dinnerware
37 Air curtains for entranceways in food and food service establishments
40 Residential wastewater treatment systems
41 Non-liquid saturated treatment systems
42 Drinking water treatment units – Aesthetic effects
44 Residential cation exchange water softeners
46 Evaluation of components and devices used in wastewater treatment systems
49 Biosafety cabinetry: Design, construction, performance, and field certification
50 Equipment for swimming pools, spas, hot tubs, and other recreational water facilities
51 Food equipment materials

NOT FOR
52 Supplemental flooring
53 Drinking water treatment units – Health effects
55 Ultraviolet microbiological water treatment systems
58 Reverse osmosis drinking water treatment systems
59 Mobile food carts
60 Drinking water treatment chemicals – Health effects
61 Drinking water system components – Health effects

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62 Drinking water distillation systems
140 Sustainable carpet assessment
169 Special purpose food equipment and devices
170 Glossary of food equipment terminology
173 Dietary supplements
177 Shower filtration systems – Aesthetic effects

OR SALE
184 Residential dishwashers
222 Ozone generators
223 Conformity assessment requirements for certification bodies that certify products pursuant to NSF/ANSI 60: Drinking water treatment chemicals –
health effects
240 Drainfield trench product sizing for gravity dispersal onsite wastewater treatment and dispersal systems
245 Wastewater treatment systems - nitrogen reduction
305 Personal care products containing organic ingredients
321 Goldenseal root (Hydrasitis canadensis)
330 Glossary of drinking water treatment unit terminology
332 Sustainability assessment for resilient floor coverings
336 Sustainability assessment for commercial furnishings fabric
342 Sustainability assessment for wallcovering products
347 Sustainability assessment for single ply roofing membranes
350 Onsite residential and commercial water reuse treatment systems
350-1Onsite residential and commercial graywater treatment systems for subsurface discharge
355 Greener chemicals and processes information
358-1Polyethylene pipe and fittings for water-based ground-source “geothermal” heat pump systems
358-2Polypropylene pipe and fittings for water-based ground-source “geothermal” heat pump systems
359 Valves for crosslinked polyethylene (PEX) water distribution tubing systems
360 Wastewater treatment systems – Field performance verification
363 Good manufacturing practices (GMP) for pharmaceutical excipients
372 Drinking water treatment system components – Lead content
401 Drinking water treatment units - Emerging compounds / incidental contaminants
418 Residential wastewater effluent filters longevity testing
14159-1 Hygiene requirements for the design of meat and poultry processing equipment
14159-2 Hygiene requirements for the design of hand held tools used in meat and poultry processing equipment
14159-3 Hygiene requirements for the design of mechanical belt conveyors used in meat and poultry processing equipment

15
The information contained in this Standards page is not part of this American National Standard (ANS) and has not
been processed in accordance with ANSI’s requirements for an ANS. Therefore, this Standards page may contain
material that has not been subjected to public review or a consensus process. In addition, it does not contain
requirements necessary for conformance to the Standard.
12/18/2014