Quality System Comparison - Completed

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Quality Management System Comparison

Instructions: Enter the text from the corresponding documents below the document heading;
ISO 9001, IPEC-PQG, and ICH Q10. The ISO 9001 text should include both ISO 9001:2008
and the draft GMP Annex. The IPEC-PQG text is from the IPEC-PQG Excipient GMP guide.
4
Quality Management System
ISO 9001:
IPEC-PQG:
ICH Q10
4.1 General Requirements
ISO 9001:
The organization shall establish, document, implement and maintain a quality management
system and continually improve its effectiveness in accordance with the requirements of this
International Standard.
The organization shall
a) determine the processes needed for the quality management system and their
application throughout the organization (see 1.2),
b) determine the sequence and interaction of these processes,
c) determine criteria and methods needed to ensure that both the operation and control of
these processes are effective,
d) ensure the availability of resources and information necessary to support the operation
and monitoring of these processes,
e) monitor, measure where applicable, and analyse these processes, and
f) implement actions necessary to achieve planned results and continual improvement of
these processes.
These processes shall be managed by the organization in accordance with the requirements
of this International Standard.
Where an organization chooses to outsource any process that affects product conformity with
requirements, the organization shall ensure control over such processes. Control of such
outsourced processes shall be identified within the quality management system.
NOTE 1 Processes needed for the quality management system referred to above include
processes for management activities, provision of resources, product realization and
measurement, analysis and improvement.
NOTE 2 An outsourced process: is a process that the organization needs for the quality
management system and which the organization chooses to have performed by and external
party.
NOTE 3 Ensuring control over outsourced processes does not absolve the organization of
the responsibility of conformity to all customer, statutory and regulatory requirements. The
type and extent of control to be applied to the outsourced process can be influenced by the
factors such as
a) The potential impact of the outsourced process on the organizations capability to
provide product that conforms to requirements,
b) The degree to which the control for the process is shared,
c) The capability of achieving the necessary control through the application of 7.4.
GMP Annex:
Where manufacturing, testing or other operations that could affect excipient quality are
outsourced, the organization shall demonstrate that the applicable GMP principles in
accordance with this Annex are applied to those operations. (see 7.4.1)
IPEC-PQG:
The principles outlined in this Guide provide a comprehensive basis for the quality
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management system used in the manufacture of pharmaceutical excipients. Excipient
manufacturers should identify the quality management processes required to assure excipient
quality.
Where manufacturing, testing or other operations that could affect excipient quality are
outsourced the responsibility for quality remains with the excipient manufacturer and control
measures should be defined (see also 7.4.2).
ICH Q10
1.5
ICH Q10 Objectives
Implementation of the Q10 model should result in achievement of three main objectives which
complement or enhance regional GMP requirements.
1.5.1 Achieve Product Realisation
To establish, implement and maintain a system that allows the delivery of products with the
quality attributes appropriate to meet the needs of patients, health care professionals,
regulatory authorities (including compliance with approved regulatory filings) and other
internal and external customers.
1.5.2 Establish and Maintain a State of Control
To develop and use effective monitoring and control systems for process performance and
product quality, thereby providing assurance of continued suitability and capability of
processes. Quality risk management can be useful in identifying the monitoring and control
systems.
1.5.3 Facilitate Continual Improvement
To identify and implement appropriate product quality improvements, process improvements,
variability reduction, innovations and pharmaceutical quality system enhancements, thereby
increasing the ability to fulfil quality needs consistently. Quality risk management can be
useful for identifying and prioritising areas for continual improvement.
1.6
Enablers: Knowledge Management and Quality Risk Management
Use of knowledge management and quality risk management will enable a company to
implement ICH Q10 effectively and successfully. These enablers will facilitate achievement of
the objectives described in Section 1.5 above by providing the means for science and risk
based decisions related to product quality.
1.6.1 Knowledge Management
Product and process knowledge should be managed from development through the
commercial life of the product up to and including product discontinuation. For example,
development activities using scientific approaches provide knowledge for product and
process understanding. Knowledge management is a systematic approach to acquiring,
analysing, storing and disseminating information related to products, manufacturing
processes and components. Sources of knowledge include, but are not limited to prior
knowledge (public domain or internally documented); pharmaceutical development studies;
technology transfer activities; process validation studies over the product lifecycle;
manufacturing experience; innovation; continual improvement; and change management
activities.
1.6.2 Quality Risk Management
Quality risk management is integral to an effective pharmaceutical quality system. It can
provide a proactive approach to identifying, scientifically evaluating and controlling potential
risks to quality. It facilitates continual improvement of process performance and product
quality throughout the product lifecycle. ICH Q9 provides principles and examples of tools for
quality risk management that can be applied to different aspects of pharmaceutical quality.
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1.7
Design and Content Considerations
(a) The design, organisation and documentation of the pharmaceutical quality system
should be well structured and clear to facilitate common understanding and consistent
application.
(b) The elements of ICH Q10 should be applied in a manner that is appropriate and
proportionate to each of the product lifecycle stages, recognising the different goals
and knowledge available for each stage.
(d) The pharmaceutical quality system should include appropriate processes, resources
and responsibilities to provide assurance of the quality of outsourced activities and
purchased materials as described in Section 2.7.
(c) Management responsibilities, as described in Section 2, should be identified within the
pharmaceutical quality system.
(d) The pharmaceutical quality system should include the following elements, as
described in Section 3: process performance and product quality monitoring,
corrective and preventive action, change management and management review.
(e) Performance indicators, as described in Section 4, should be identified and used to
monitor the effectiveness of processes within the pharmaceutical quality system.
4.2 Documentation Requirements
ISO 9001:
4.2.1 General
The quality management system documentation shall include
a) documented statements of a quality policy and quality objectives,
b) a quality manual,
c) documented procedures required by this International Standard,
d) documents needed by the organization to ensure the effective planning, operation and
control of its processes, and
e) records required by this International Standard (see 4.2.4).
NOTE 1 Where the term documented procedure appears within this International Standard,
this means that the procedure is established, documented, implemented and maintained. A
single document may address the requirements for one or more procedures. A requirement
for a documented procedure may be covered by more than one document.
NOTE 2 The extent of the quality management system documentation can differ from one
organization to another due to
a) the size of organization and type of activities,
b) the complexity of processes and their interactions, and
c) the competence of personnel.
NOTE 3 The documentation can be in any form or type of medium.
GMP Annex:
The quality management system documentation shall include:
d) documented procedures required in this Annex.
4.2.2 Quality manual
The organization shall establish and maintain a quality manual that includes
a) the scope of the quality management system, including details of and justification for
any exclusions (see 1.2),
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b) the documented procedures established for the quality management system, or
reference to them, and
c) a description of the interaction between the processes of the quality management
system.
GMP Annex
The organization shall establish and maintain a quality manual that includes or references:
d) a definition of the extent to which this Annex applies to its quality management system
and its business processes, and
e) a definition of the point at which GMP applies to the manufacturing process.
4.2.3 Control of documents
Documents required by the quality management system shall be controlled. Records are a
special type of document and shall be controlled according to the requirements given in 4.2.4.
A documented procedure shall be established to define the controls needed
a) to approve documents for adequacy prior to issue,
b) to review and update as necessary and re-approve documents,
c) to ensure that changes and the current revision status of documents are identified,
d) to ensure that relevant versions of applicable documents are available at points of use,
e) to ensure that documents remain legible and readily identifiable,
f) to ensure that documents of external origin are identified and their distribution
controlled, and
g) to prevent the unintended use of obsolete documents, and to apply suitable
identification to them if they are retained for any purpose.
GMP Annex
Documents that impact product quality shall have a defined owner and be reviewed and
approved by the Quality Unit before issue. (See also 5.5.1).
If electronic signatures are used on documents they shall be controlled to provide equivalent
security to that given by a hand written signature.
4.2.4 Control of records
Records shall be established and maintained to provide evidence of conformity to
requirements and of the effective operation of the quality management system. Records shall
remain legible, readily identifiable and retrievable. A documented procedure shall be
established to define the controls needed for the identification, storage, protection, retrieval,
retention time and disposition of records.
GMP Annex
Records shall include pertinent subcontractor quality data. Electronic records shall be subject
to the same controls as those required for other records.
Entries in quality records shall be clear, indelible and made directly after performing the
activity (in the order performed), signed and dated by the person making the entry.
Corrections to entries shall be signed and dated, leaving the original entry still legible.
IPEC-PQG:
4.2.1 General
The excipient manufacturer should have a system in place to control documents and data that
relate to the requirements of the quality management system.
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4.2.2 Quality Manual
The excipient manufacturer should prepare a quality manual describing the quality
management system, the quality policy and the commitment of the excipient manufacturer to
applying the appropriate GMP and quality management standards contained in this Guide.
This manual should include the scope of the quality management system, reference to
supporting procedures and a description of the interaction between quality management
processes.
4.2.3 Control of Documents
The excipient manufacturer should establish and maintain procedures for the identification,
collection, indexing, filing, storage, maintenance and disposition of controlled documents,
including documents of external origin that are part of the quality management system.
Procedures used in the manufacture of excipients should be documented, implemented and
maintained. In addition, there should be formal controls relating to procedure approval,
revision and distribution. These controls should provide assurance that the current version of
a procedure is being used throughout the operational areas and previous revisions of
documents have been removed.
Documents and subsequent changes to documents should be reviewed and approved by
designated qualified personnel before issuance to the appropriate areas, as identified in the
documents. Documents that impact product quality should be reviewed and approved by the
quality unit (see also 5.5.1).
Controlled documents may include a unique identifier, date of issue and revision number to
facilitate identification of the most recent document. The department with the responsibility for
issuing the documents should be identified. Where practical, changes and the reasons for the
change should be documented.
Electronic documentation should meet the requirements for the document control system
stated above. If electronic signatures are used on documents, they should be controlled to
provide equivalent security to that given by a handwritten signature. Electronic documents
and signatures may also need to satisfy local regulatory requirements.
4.2.4 Control of Records
The excipient manufacturer should establish and maintain procedures for the identification,
collection, indexing, filing, storage, maintenance and disposition of records.
Records should be maintained to demonstrate achievement of the required quality and the
effective operation of the quality management system. Records should be legible and
identifiable with the product involved. Pertinent subcontractor quality data should be an
element of these records.
Entries in records should be clear, indelible, made directly after performing the activity (in the
order performed), signed and dated by the person making the entry. Corrections to entries
should be signed and dated, leaving the original entry legible.
Records should be kept for a defined period. This period should be appropriate to the
excipient, its expiry date or re-evaluation interval. Records should be stored and maintained
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in such a manner that they are readily retrievable, in facilities that provide a suitable
environment to minimize deterioration or damage.
ICH Q10
4.2.1 General
1.7
(a) The design, organisation and documentation of the pharmaceutical quality system
should be well structured and clear to facilitate common understanding and consistent
application.
(c) The size and complexity of the companys activities should be taken into consideration
when developing a new pharmaceutical quality system or modifying an existing one.
The design of the pharmaceutical quality system should incorporate appropriate risk
management principles. While some aspects of the pharmaceutical quality system can
be company-wide and others site-specific, the effectiveness of the pharmaceutical
quality system is normally demonstrated at the site level.
4.2.2 Quality Manual
1.8
Quality Manual
A Quality Manual or equivalent documentation approach should be established and should

contain the description of the pharmaceutical quality system. The description should include:
(b) The quality policy (see Section 2);
(f) The scope of the pharmaceutical quality system;
(g) Identification of the pharmaceutical quality system processes, as well as their
sequences, linkages and interdependencies. Process maps and flow charts can be
useful tools to facilitate depicting pharmaceutical quality system processes in a visual
manner;
Management responsibilities within the pharmaceutical quality system (see Section 2).
4.2.3 Control of Documents
No requirements
4.2.4 Control of Records
No requirements
4.3 Change Control
ISO 9001:
GMP Annex
There shall be a documented procedure for the evaluation and approval of changes that may
impact upon the quality of the excipient. The evaluation and approval of changes shall occur
prior to the implementation of the changes. A unit independent from production shall approve
changes that may impact on the quality of the excipient. Where the impact on the quality of
the excipient is significant, change1 shall be communicated to customers and, as applicable,
regulatory authorities (see 7.2.3).
The responsibilities and requirements for evaluating, managing, implementing change and
maintaining records (see 4.2.4) shall be defined in a documented procedure.
IPEC-PQG:
4.3 Change Control
The excipient manufacturer should establish and maintain procedures to evaluate and
1
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approve changes that may have an impact on the quality of the excipient. For example, this
may include changes to:
raw materials or packaging and their sources,
material specifications,
test methods,
manufacturing and analytical equipment,
production processes,
manufacturing or packaging sites etc.
A function that is independent from production (such as regulatory affairs, quality assurance,
etc.) should have the responsibility and authority for the final approval of changes.
Customers and, if necessary, regulatory authorities [for example, for Drug Master Files
(DMFs) or Certificates of Suitability to the European Pharmacopoeia (CEPs)] should be
notified of significant changes from established production and process control procedures
that may affect excipient quality (see also 7.2.3 and Appendix C). The IPEC-Americas
Significant Change Guide for Bulk Pharmaceutical Excipients provides criteria that the
excipient manufacturer can use to determine when to involve the pharmaceutical customer,
based on the likelihood that a proposed change will impact their drug product.
IPEC Americas Significant Change Guide Version 2 2009
ICH Q10
4.3 Change Control
1.7
(f) The pharmaceutical quality system should include the following elements, as
described in Section 3: process performance and product quality monitoring,
corrective and preventive action, change management and management review.
5 Management Responsibility
ISO 9001:
No text title is a header only
IPEC-PQG:
No Text
ICH Q10
2. MANAGEMENT RESPONSIBILITY
Leadership is essential to establish and maintain a company-wide commitment to quality and
for the performance of the pharmaceutical quality system.
5.1 Management Commitment
ISO 9001:
Top management shall provide evidence of its commitment to the development and
implementation of the quality management system and continually improving its effectiveness
by
a) communicating to the organization the importance of meeting customer as well as
statutory and regulatory requirements,
b) establishing the quality policy,
c) ensuring that quality objectives are established,
d) conducting management reviews, and
e) ensuring the availability of resources.
GMP Annex:
f) ensuring that GMP objectives are established, and
g) communicating to the organization the importance of conforming to GMP.
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IPEC-PQG:
Top management should demonstrate to the organisation the importance it places on
customer satisfaction and compliance with the appropriate regulations and standards.
This should be accomplished through the development of a quality policy and
establishment of quality objectives. Progress towards the documented quality objectives
should be reviewed at planned intervals
ICH Q10
(a) Senior management has the ultimate responsibility to ensure an effective
pharmaceutical quality system is in place to achieve the quality objectives, and that
roles, responsibilities, and authorities are defined, communicated and implemented
throughout the company.
(b) Management should:
(1) Participate in the design, implementation, monitoring and maintenance of an
effective pharmaceutical quality system;
(2) Demonstrate strong and visible support for the pharmaceutical quality system and
ensure its implementation throughout their organisation;
(3) Ensure a timely and effective communication and escalation process exists to
raise quality issues to the appropriate levels of management;
(4) Define individual and collective roles, responsibilities, authorities and interrelationships of all organisational units related to the pharmaceutical quality
system. Ensure these interactions are communicated and understood at all levels
of the organisation. An independent quality unit/structure with authority to fulfil
certain pharmaceutical quality system responsibilities is required by regional
regulations;
(5) Conduct management reviews of process performance and product quality and of
the pharmaceutical quality system;
(6) Advocate continual improvement;
(7) Commit appropriate resources.
5.2 Customer Focus
ISO 9001:
Top management shall ensure that customer requirements are determined and are met with
the aim of enhancing customer satisfaction (see 7.2.1 and 8.2.1).
GMP Annex:
The organization shall enable the customer to assess the continued effectiveness of its
quality management system, records, manufacturing processes, buildings and facilities.
5.2 Customer Focus
IPEC-PQG:
It is the responsibility of top management to ensure that customer requirements are
determined and met.
The excipient manufacturer should permit the customer or their representative to conduct
audits to review its quality management system, manufacturing processes, buildings and
facilities.
5.2 Customer Focus
ICH Q10
As pharmaceutical manufacturers are the end of the manufacturing chain, customers are
then consumers of their products and not further actors in the supply chain. In this regard
we have to translate the ISO term customer to mean regulator and government.
I could not find any succinct sections in ICH Q10 that mapped simply to this section.
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5.3 Quality Policy
ISO 9001:
Top management shall ensure that the quality policy
a) is appropriate to the purpose of the organization,
b) includes a commitment to comply with requirements and continually improve the
effectiveness of the quality management system,
c) provides a framework for establishing and reviewing quality objectives,
d) is communicated and understood within the organization, and
e) is reviewed for continuing suitability.
GMP Annex:
Top management shall ensure that the quality policy:
f) includes a commitment to the implementation of GMP.
IPEC-PQG:
5.3 Quality Policy
Top management should demonstrate its commitment to the corporate quality policy and
ensure that it is implemented within the operational unit. The quality policy should support
continual improvement of the quality management system. Management should participate in
the development of the company's quality policy and provide the resources necessary for its
development, maintenance and deployment.
ICH Q10
5.3 Quality Policy
2.2 Quality Policy
(a) Senior management should establish a quality policy that describes the overall
intentions and direction of the company related to quality.
(b) The quality policy should include an expectation to comply with applicable regulatory
requirements and should facilitate continual improvement of the pharmaceutical
quality system.
(c) The quality policy should be communicated to and understood by personnel at all
levels in the company.
(d) The quality policy should be reviewed periodically for continuing effectiveness.
5.4 Planning
ISO 9001:
5.4.1 Quality objectives
Top management shall ensure that quality objectives, including those needed to meet
requirements for product [see 7.1 a)], are established at relevant functions and levels within
the organization. The quality objectives shall be measurable and consistent with the quality
policy.
GMP Annex:
5.4.1 Quality objectives
Top management shall set objectives for adherence to GMP.
5.4.2 Quality management system planning
Top management shall ensure that
a) the planning of the quality management system is carried out in order to meet the
requirements given in 4.1, as well as the quality objectives, and
b) the integrity of the quality management system is maintained when changes to the
quality management system are planned and implemented.
GMP Annex
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5.4.2 Quality Management system planning
No additional requirements.
IPEC-PQG:
5.4.1 Quality Objectives
Top management should set objectives for adherence to GMP to ensure that the excipient
manufacturer maintains and improves its performance. Objectives should be deployed
throughout the organisation and should be measurable and consistent with the quality policy.
5.4.2 Quality Management System Planning
Top management should provide adequate resources to ensure conformance to the
provisions of this Guide. There should be a process for the identification of resources needed
for adherence to GMP. A gap analysis based on audits by internal personnel, customers,
regulatory agencies or outside contractors and this Guide could be used for the purpose of
identifying resource requirements.
Top management should ensure that the integrity of the quality management system is
maintained when changes are planned and implemented.
ICH Q10
5.4 Planning
2.3 Quality Planning
(a) Senior management should ensure the quality objectives needed to implement the
quality policy are defined and communicated.
(b) Quality objectives should be supported by all relevant levels of the company.
(c) Quality objectives should align with the companys strategies and be consistent with
the quality policy.
(d) Management should provide the appropriate resources and training to achieve the
quality objectives.
(e) Performance indicators that measure progress against quality objectives should be
established, monitored, communicated regularly and acted upon as appropriate as
described in Section 4.1 of this document
5.5 Responsibility, Authority and Communication
ISO 9001:
5.5.1 Responsibility and authority
Top management shall ensure that responsibilities and authorities are defined and
communicated within the organization.
GMP Annex:
5.5.1 Responsibility and authority
A unit independent from production such as the Quality Unit shall be responsible for:
ensuring quality critical activities are undertaken as defined,
approving suppliers of quality critical materials and services,
approving or rejecting raw materials, packaging components, intermediates and
finished excipients,
reviewing production records to ensure that if errors have occurred, they have
been fully investigated,
approving changes to quality critical equipment, processes, specifications,
procedures, test methods (see 4.3),
investigating failures and complaints
approving or rejecting the excipient if it is manufactured, processed, packaged, or
held under contract by another company, and
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developing and implementing an internal audit program.
This independent unit is referred to as the Quality Unit throughout this document and
may delegate some of these activities if appropriate controls are in place and are
documented.
Documentation showing the inter-departmental relationships as well as relationship to
top management shall demonstrate the independence of the Quality Unit.
Personnel whose role has an impact on excipient quality shall have written job
descriptions.
5.5.2 Management representative
Top management shall appoint a member of the organization's management who,
irrespective of other
responsibilities, shall have responsibility and authority that includes
a) ensuring that processes needed for the quality management system are established,
implemented and maintained,
b) reporting to top management on the performance of the quality management system
and any need for improvement, and
c) ensuring the promotion of awareness of customer requirements throughout the
organization.
NOTE The responsibility of a management representative can include liaison with external
parties on matters relating to the quality management system.
GMP Annex
5.5.3 Internal communication
Top management shall ensure that appropriate communication processes are established
within the organization and that communication takes place regarding the effectiveness of the
quality management system.
GMP Annex
GMP and regulatory requirements shall be communicated as appropriate to roles in the
organization.
Top management shall be promptly notified about any quality critical situations in
accordance with a documented procedure.
IPEC-PQG:
5.5.1 Responsibility and Authority
Responsibility and authority should be clearly defined by top management and
communicated within the organisation.
It should be the responsibility of a unit independent of production, such as the quality
unit, to:
ensure quality-critical activities are undertaken as defined,
approve suppliers of quality-critical materials and services,
approve or reject raw materials, packaging components, intermediates and
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finished excipients,
ensure that there is a review of production records to ensure that no errors have
occurred or, if errors occur, that they are fully investigated,
participate in reviewing and authorising changes to processes, specifications,
procedures and test methods that potentially affect quality (see also 4.3) and in
investigating failures and complaints,
retain responsibility for approval or rejection of the excipient if it is produced,
processed, packaged or held under contract by another company,
develop and implement a self inspection programme of the quality management
system.
The excipient manufacturer may delegate some of the quality units activities to other
personnel if appropriate controls (for example periodic audits, training and
documentation) are in place.
An organisation chart by function should show inter-departmental relationships as well
as relationships to top management of the company. Personnel who have an impact on
excipient quality should have job descriptions.
5.5.2 Management Representative
The excipient manufacturer should appoint a management representative with sufficient
authority to ensure that the provisions of this Guide are properly implemented. The
representative should periodically report to top management on conformance to the
quality management system, including changing customer and regulatory requirements.
5.5.3 Internal Communication
The excipient manufacturer should ensure appropriate systems are established to
communicate GMP and regulatory requirements, quality policies, quality objectives and
procedures throughout the organisation. The communication should also provide
information about the effectiveness of the quality management system.
Top management should be notified in a timely manner of quality-critical situations,
such as product retrievals, in accordance with a documented procedure.
ICH Q10
5.5 Management Responsibility
2.5 Internal Communication
(a) Management should ensure appropriate communication processes are established
and implemented within the organisation.
(b) Communications processes should ensure the flow of appropriate information
between all levels of the company.
(c) Communication processes should ensure the appropriate and timely escalation of
certain product quality and pharmaceutical quality system issues.
5.6 Management Review
ISO 9001:
5.6.1 General
Top management shall review the organization's quality management system, at planned
intervals, to ensure its continuing suitability, adequacy and effectiveness. This review shall
include assessing opportunities for improvement and the need for changes to the quality
management system, including the quality policy and quality objectives.
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Records from management reviews shall be maintained (see 4.2.4).
5.6.2 Review input
The input to management review shall include information on
a) results of audits,
b) customer feedback,
c) process performance and product conformity,
d) status of preventive and corrective actions,
e) follow-up actions from previous management reviews,
f) changes that could affect the quality management system, and
g) recommendations for improvement.
5.6.3 Review output
The output from the management review shall include any decisions and actions related to
a) improvement of the effectiveness of the quality management system and its
processes,
b) improvement of product related to customer requirements, and
c) resource needs.
GMP Annex:
No additional requirements
IPEC-PQG:
5.6.1 General
The top management of the company should hold periodic reviews of the quality
management system to confirm the organisations continued conformance to this
Guide.
The review should be recorded and include assessing opportunities for improvement
and the need for changes to the quality management system.
5.6.2 Review Input
Management review inputs should include for example:
results of internal and external audits,
customer feedback of the company performance,
product conformity and process performance,
action items from the previous management review,
customer complaints,
status of corrective or preventive actions,
changes that could affect the quality management system.
5.6.3 Review Output
The management review should identify the resources needed and opportunities
presented for improvement of the quality management system and improvement of
product conformance to customer and regulatory requirements. A record should be
made of actions recommended and taken.
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ICH Q10
(a) Senior management should be responsible for pharmaceutical quality system
governance through management review to ensure its continuing suitability and
effectiveness.
(b) Management should assess the conclusions of periodic reviews of process
performance and product quality and of the pharmaceutical quality system, as
described in Sections 3 and 4.
3.2.4 Management Review of Process Performance and Product Quality
Management review should provide assurance that process performance and product quality
are managed over the lifecycle. Depending on the size and complexity of the company,
management review can be a series of reviews at various levels of management and should
include a timely and effective communication and escalation process to raise appropriate
quality issues to senior levels of management for review.
(a) The management review system should include:
(1) The results of regulatory inspections and findings, audits and other
assessments, and commitments made to regulatory authorities;
(2) Periodic quality reviews, that can include:
(i)
Measures of customer satisfaction such as product quality
complaints and recalls;
(ii)
Conclusions of process performance and product quality
monitoring;
(iii)
The effectiveness of process and product changes including
those arising from corrective action and preventive actions.
(3) Any follow-up actions from previous management reviews.
(b) The management review system should identify appropriate actions, such as:
(1) Improvements to manufacturing processes and products;
(2) Provision, training and/or realignment of resources;
(3) Capture and dissemination of knowledge.
Table IV: Application of Management Review of Process Performance and Product
Quality throughout the Product Lifecycle
Pharmaceutical
Technology
Commercial
Product
Development
Transfer
Manufacturing
Discontinuation
Aspects of
Aspects of
Management review Management review
management review management review should be a
should include such
can be performed to should be
structured system,
items as product
ensure adequacy of
performed to ensure as described above, stability and product
the product and
the developed
and should support
quality complaints.
process design.
product and process continual
can be
improvement.
manufactured at
commercial scale.
4.1 Management Review of the Pharmaceutical Quality System
Management should have a formal process for reviewing the pharmaceutical quality system
on a periodic basis. The review should include:
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(a) Measurement of achievement of pharmaceutical quality system objectives;
(b) Assessment of performance indicators that can be used to monitor the
effectiveness of processes within the pharmaceutical quality system, such as:
(1)
(2)
(3)
(4)
Complaint, deviation, CAPA and change management processes;

Feedback on outsourced activities;
Self-assessment processes including risk assessments, trending, and audits;
External assessments such as regulatory inspections and findings and
customer audits
4.2 Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality
System
Factors monitored by management can include:
(a) Emerging regulations, guidance and quality issues that can impact the Pharmaceutical
Quality System;
(b) Innovations that might enhance the pharmaceutical quality system;
(c) Changes in business environment and objectives;
(d) Changes in product ownership.
4.3 Outcomes of Management Review and Monitoring
The outcome of management review of the pharmaceutical quality system and monitoring of
internal and external factors can include:
(e) Improvements to the pharmaceutical quality system and related processes;
(f) Allocation or reallocation of resources and/or personnel training;
(g) Revisions to quality policy and quality objectives;
(h) Documentation and timely and effective communication of the results of the
management review and actions, including escalation of appropriate issues to senior
management.
6
Resource Management
ISO 9001:
No requirement
IPEC-PQG:
No requirement
ICH Q10
Section 2.4 a. Management should determine and provide adequate and appropriate
resources (human, financial, materials, facilities and equipment) to implement and maintain
the pharmaceutical quality system and continually improve its effectiveness
6.1 Provision of Resources
ISO 9001:
The organization shall determine and provide the resources need
a) to implement and maintain the quality management system and continually improve its
effectiveness, and
b) to enhance customer satisfaction by meeting customer requirements
GMP Annex
C) to meet the GMP requirements of this Annex.
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IPEC-PQG:
There should be sufficient qualified personnel and resources (e.g., equipment, materials,
buildings and facilities) to implement, maintain and improve the quality management system
and to produce, package, test, store and release each excipient in a manner consistent with
this Guide
ICH Q10
Section 2.4 b. Management should ensure that resources are appropriately applied to a
specific product, process or site.
6.2 Human Resources
ISO 9001:
6.2.1. General
Personnel performing work affecting product quality shall be competent on the basis of
appropriate education, training, skills and experience
GMP Annex
Records shall be maintained listing the name, address and qualifications of consultants who
provide advice concerning any aspect of the Quality Management System and the type of
service they provide.
6.2.2 Competence, awareness and training
The organization shall:
a) determine the necessary competence for personnel performing work affecting product
quality,
b) provide training or take other actions to satisfy these needs,
c) evaluate the effectiveness of the actions taken
d) ensure that its personnel are aware of the relevance and importance of their activities
and how they contribute to the achievement of the quality objectives, and
e) maintain appropriate records of education, training, skill and experience
GMP Annex
f) ensure training, including GMP as it relates to the employees function, is conducted
by qualified individuals, and ,
g) ensure GMP refresher training is conducted periodically
GMP Annex
6.2.3 Personnel Hygiene
Where excipients are exposed to potential environmental contaminants, the organization shall
apply appropriate controls to ensure the product is not contaminated.
Personnel shown to have an apparent illness or open lesions that may adversely affect the
safety or quality of the excipient shall be excluded from direct contact with raw materials,
packaging components, intermediates, and finished excipient.
The storage and use of food, drink, personal medication, tobacco products or similar items
shall be restricted to certain designated locations separate from manufacturing areas.
IPEC-PQG:
6.2.1 General
Personnel performing work affecting the quality of excipients should have the appropriate
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combination of education, training and experience for their assigned tasks.
Consultants advising on the design, production, packaging, testing or storage of excipients
should have sufficient education, training and experience or any combination thereof to
advise on the subject for which they are retained. Records should be maintained listing the
name, address and qualifications of consultants and the type of service they provide.
6.2.2 Competence, Awareness and Training
The excipient manufacturer should establish and maintain procedures for identifying training
needs and providing the necessary training to personnel performing activities affecting
excipient quality. Appropriate records of training should be maintained. Training should
address the particular operations that the employee performs and GMP as it relates to the
employees functions. Qualified individuals should conduct GMP training with sufficient
frequency to ensure that employees remain familiar with applicable GMP principles.
Management should establish adequate and continued personal hygiene training for
personnel who handle materials so that they understand the precautions necessary to
prevent contamination of excipients.
The training program should ensure personnel understand that deviations from procedures
may have an impact on the customers product quality.
6.2.3 Personnel Hygiene
To protect excipients from contamination protective apparel such as head, face, hand and
arm coverings should be worn as appropriate to the duties performed. Jewelry and other
loose items, including those in pockets, should be removed or covered. Only authorized
personnel should enter those areas of the buildings and facilities designated as limited
access areas.
Personnel should practice good sanitation and health habits. Any person shown to have an
apparent illness or open lesions (by either medical examination or supervisory observation)
that may adversely affect the safety or quality of the excipient should be excluded from direct
contact with raw materials, packaging components, intermediates and finished excipients until
the condition is corrected or determined by competent personnel not to jeopardize the safety
or quality of the excipient. Personnel should be instructed to report to supervisory personnel
any health conditions that may have an adverse effect on excipients.
The storage and use of food, drink, personal medication, tobacco products or similar items
should be restricted to certain designated locations separate from manufacturing areas.
ICH Q10
No requirement
6.3 Infrastructure
ISO 9001:
The organization shall determine, provide and maintain the infrastructure needed to achieve
conformity to product requirements, infrastructure includes, as applicable
a) buildings, workspace and associated utilities
b) process equipment (both hardware and software), and
c) supporting services (such as transport or communication)
GMP Annex
The infrastructure shall be managed, operated, cleaned and maintained in and to avoid
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contamination of raw materials, intermediates and the excipient. Where the infrastructure is
critical to excipient quality, the controls shall be documented.
Equipment which may impact excipient quality shall be commissioned before use to ensure
that it is functioning as intended. The use, cleaning and maintenance of quality critical
equipment shall be recorded.
Production processes associated with highly sensitizing or toxic materials shall be in
dedicated equipment separate from that used for excipient manufacture, unless appropriate
measures to avoid cross-contamination have been implemented and the effectiveness of
these measures have been demonstrated.
Process materials which are intended to come into contact with the excipient (e.g. lubricants,
steam additives, filter media etc) shall be controlled to ensure that they are appropriate for
the intended use.
Computerized systems that may impact upon excipient quality shall have sufficient controls
for operation, maintenance, back-up or archiving, and measures to prevent unauthorized
access or changes to software, hardware or data.
Water used in the manufacture of excipients shall be monitored to confirm it is of a suitable
quality for its intended use.
Storage containers and their attendant manifolds, filling and discharge lines shall be
identified.
IPEC-PQG:
6.3 Infrastructure
The infrastructure should be managed, operated, cleaned and maintained in accordance with
GMP principles to ensure excipient quality and to avoid contamination (including, where
critical to excipient quality, control of particulate matter, microbiological control and control of
water quality).
6.3.1 Buildings and Facilities
The prevention of contamination should be considered in the design of the manufacturing
processes and facilities, particularly where the excipient is exposed. Buildings and facilities
used in the production, processing, packaging, testing or storage of an excipient should be
maintained in a good state of repair and should be of suitable size, construction and location
to facilitate cleaning, maintenance and correct operation appropriate to the type of
processing.
Manufacturing processes associated with the production of highly sensitizing or toxic products
(for example, herbicides, pesticides etc.) should be located in dedicated facilities or use
equipment separate from that used for excipient manufacture. If this is not possible then
appropriate measures (for example, cleaning, inactivation) should be implemented to avoid
cross-contamination. The effectiveness of these measures should be demonstrated.
There should be adequate facilities for the testing of raw materials, packaging components,
intermediates and finished excipients.
6.3.2 Equipment
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Equipment used in the production, processing, packaging, testing or storage of an excipient
should be maintained in a good state of repair and should be of suitable size, construction
and location to facilitate cleaning, maintenance and correct operation, depending on the type
of processing (for example, batch versus continuous).
Equipment should be commissioned before use to ensure that it is functioning as intended.
Where equipment is located outdoors there should be suitable control to minimize the risk to
excipient quality from the environment (for example, processing within a closed system).
6.3.2.1 Equipment Construction
Process equipment should be constructed so that contact surfaces will not be reactive,
additive or absorptive and thus not alter the quality of the excipient. Substances required
for operation, such as lubricants or coolants, should preferably not come into contact with
raw materials, packaging materials, intermediates or finished excipients. Where contact is
possible, substances suitable for use in food applications should be utilized.
Equipment should be designed to minimize the possibility of contamination caused by
direct operator contact in such activities as the unloading of centrifuge bags, use of
transfer hoses (particularly those used to transfer powders) and the operation of drying
equipment and pumps. The sanitary design of transfer and processing equipment should
be evaluated. Equipment with moving parts should be assessed with regard to the
integrity of seals and packing materials to control the risk of contamination.
6.3.2.2 Equipment Maintenance
Documented procedures should be established and followed for maintenance of critical
equipment used in the production, processing, packaging, testing or holding of the
excipient. There should be records of the use and maintenance of quality-critical
equipment. These records can be in the form of a log, computer database or other
appropriate documentation.
6.3.2.3 Computer Systems
Computer systems that may impact upon excipient quality should have sufficient controls
for operation and maintenance and to prevent unauthorized access or changes to
computer software, hardware or data, including:
systems and procedures that show the equipment and software are
performing as intended,
procedures for checking the equipment at appropriate intervals,
retention of suitable back-up or archival systems such as copies of the
program and files,
assurance that changes are verified and documented and only made
by authorized personnel.
6.3.3 Utilities
Utilities (for example, nitrogen, compressed air, steam etc.) used in the production,
storage or transfer of materials that could impact excipient quality should be assessed
and appropriate action taken to control the risk of contamination and cross-contamination.
6.3.4 Water
Water used in the manufacture of excipients should be demonstrated to be of a suitable
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quality for its intended use. Unless otherwise justified process water should, at a minimum,
meet WHO guidelines for drinking (potable) water quality.
If drinking (potable) water is insufficient to assure quality or tighter chemical and/or
microbiological water quality specifications are required, appropriate controls and
specifications should be set, for example, physical and chemical attributes, total microbial
counts, limits on objectionable organisms and/or endotoxins.
Where water used in the process is treated by the manufacturer to achieve a defined quality
the treatment process should be specified and monitored with appropriate action limits.
Water that comes into contact with the excipient should be supplied under continuous positive
pressure (or other means of preventing back flow) in a system free of defects to control the
risk of contamination to the excipient.
ICH Q10
No requirement
6.4 Work Environment
ISO 9001:
The organization shall determine and manage the work environment needed to achieve
conformity to product requirements.
GMP Annex
The work environment shall be managed and controlled to minimize risks of excipient
contamination. A documented risk assessment shall be carried out to determine the
necessary controls.
Where maintenance of the work environment is critical to excipient quality, the controls shall
be documented.
IPEC-PQG:
6.4 Work Environment
Where the excipient is exposed during manufacture it should be in an appropriate
environment to minimize contamination. The manufacturer should apply suitable controls to
maintain that environment.
6.4.1 Air Handling
Where an air handling system is installed to provide protection to the excipient, the excipient
manufacturer should demonstrate its effectiveness.
Excipient production unit air handling systems should be designed to prevent cross
contamination. For dedicated areas processing the same excipient it is permissible to recycle
a portion of the exhaust air back into the same area. The adequacy of such a system for
multi-use areas, especially if several products are processed simultaneously, should be
assessed for potential cross-contamination.
6.4.2 Controlled Environment
A controlled environment may be necessary to avoid contamination or degradation caused by
exposure to heat, air or light. The degree of protection required may vary depending on the
stage of the process.
Special environments required by some processes should be monitored to assure product
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quality (for example, inert atmosphere or protection from light). Where an inert atmosphere is
required, the gas should be treated as a raw material. If interruptions in the special
environment occur adequate evidence and appropriate rationale should be documented to
show that such interruptions have not compromised the quality of the excipient. Such
environmental concerns become increasingly important following purification of the excipient.
6.4.3 Cleaning and Sanitary Conditions
Adequate cleanliness is an important consideration in the design of excipient manufacturing
facilities. Buildings used in the production, processing, packaging or holding of an excipient
should be maintained in an appropriately clean and sanitary condition according to the type of
processing conducted (for example, open/closed systems).
Where maintenance of clean and sanitary conditions is critical to excipient quality,
documented procedures should assign responsibility for cleaning and sanitation, describing in
sufficient detail the cleaning schedules, methods, equipment and materials to be used in
cleaning the buildings and facilities. These procedures should be followed and cleaning
should be documented.
Waste should be segregated and disposed of in a timely and appropriate manner. If waste is
not disposed of immediately, it should be suitably identified.
6.4.4 Pest Control
Buildings should be free from infestation by rodents, birds, insects and other vermin. Some
raw materials, particularly botanicals, may contain some unavoidable contamination, such as
rodent or other animal filth or infestation. The manufacturer should have sufficient control
methods to prevent the increase of such contamination or infestation in holding areas and its
spread to other areas of the plant.
6.4.5 Lighting
Adequate lighting should be provided to facilitate cleaning, maintenance and proper
operations.
6.4.6 Drainage
In areas where the excipient is open to the environment, drains should be of adequate size
and, where connected directly to a sewer, should be provided with an air break or other
mechanical device to prevent back-siphoning.
6.4.7 Washing and Toilet Facilities
Adequate personal washing facilities should be provided, including hot and cold water, soap
or detergent, air dryers or single service towels and clean toilet facilities easily accessible to
working areas. Adequate facilities for showering and/or changing clothes should be provided,
where appropriate.
ICH Q10
No requirement
7
Product Realization
7.1 Planning of Product Realization
ISO 9001:
In planning product realization, the organization shall determine the following, as appropriate:
a) quality objectives and requirements for the product;
b) the need to establish processes and documents, and to provide resources specific to
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the product;
c) required verification , validation, monitoring, measurement, inspection and test
activities specific to the product and the criteria for product acceptance;
d) records needed to provide evidence that the realization processes and resulting
product meet requirements.
The output of this planning shall be in a form suitable for the organizations method of
operations.
GMP Annex
e) documented testing programs for quality critical materials and excipients that include
appropriate specifications, sampling plans, test and release procedures, and
f) environmental and hygiene control programs to minimize contamination of the
excipient.
IPEC-PQG:
The excipient manufacturer should plan and develop the processes and controls needed for
product manufacture.
These plans and controls should be appropriate to the production process, excipient
specification, equipment and facilities used in the manufacture of the product.
Key aspects of the planning of a suitable process and its controls should include as
appropriate:
documented testing programs for quality-critical materials including excipients that
include appropriate specifications, sampling plans, test and release procedures,
generation and maintenance of records (see also 4.2.4) that provide evidence that
these plans have been realised as intended and that enable traceability to be
demonstrated (see also 7.5.3.1),
provision of resources to implement these plans,
environmental and hygiene control programs to minimise contamination.
ICH Q10
No requirement
7.2 Customer-related Processes
ISO 9001:
7.2.1 Determination of requirements related to the product
The organization shall determine
a) requirements specified by the customer, including the requirements for delivery and
post-delivery activities,
b) requirements not stated by the customer but necessary for specified or intended use,
where known
c) statutory and regulatory requirements applicable to the product ,
d) any additional requirements considered necessary by the organisation
GMP Annex
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 related to the product. This review shall be
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conducted prior to the organisations commitment to supply a product to the customer (e.g.
submission of tenders, acceptance of contracts or orders, acceptance of changes to contracts
or orders) and shall ensure that
a) product requirements are defined
b) contract or order requirements differing from those previously expressed are resolved,
and
c) the organization has the ability to meet the defined requirements.
Records of the results of the review and actions arising from the review shall be maintained.
Where the customer provides no documented statement of requirement, the customer
requirements shall be confirmed by the organization before acceptance.
Where product requirements are changed, the organization shall ensure that relevant
documents are amended and that relevant personnel are made aware of the changed
requirements.
GMP Annex
7.2.3 Customer communication
The organization shall determine and implement effective arrangements for communicating
with customers in relation to:
a) product information
b) enquiries , contracts or order handling, including amendments
c) customer feedback, including customer complaints
GMP Annex
d) significant changes. (See also 4.3 and 7.2.1)
If production of the excipient is outsourced then this shall be communicated to the customer.
IPEC-PQG:
7.2.1 Determination of Requirements Related to the Product
The excipient manufacturer should determine the excipient quality, labelling and
delivery requirements of the customer. Additional requirements, whether customerspecific, legal or regulatory (for example pharmacopoeia material and general
monographs), should be agreed by both parties. Requirements not stated by the
customer but necessary for specified or intended use, where known, should be
considered.
7.2.2 Review of Requirements Related to the Product
The excipient manufacturer and customer should mutually agree upon the requirements
identified in 7.2.1 before supply commences. The manufacturer should have the facility
and process capability to meet consistently the mutually agreed specifications. Where
the requirements determined in 7.2.1 are changed, this review should be repeated
before supply recommences.
7.2.3
Customer Communication
There should be provision for providing accurate and pertinent communication to the
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customer. Master copies of documents such as specifications and technical reports
should be controlled documents. Provision should be made for replying to customer
enquiries, contracts and order handling requirements. Customer feedback and
complaints should be documented. Customers should be notified of significant changes
(see also 4.3). For additional change notification information refer to IPEC-Americas
Significant Change Guide for Bulk Pharmaceutical Excipients.
ICH Q10
No Text
7.3 Design and Development
ISO 9001:
7.3.1 Design and development planning
The organization shall plan and control the design and development of the product.
During the design and development planning, the organization shall determine
a) The design and development stages
b) The review, verification and validation that are appropriate to each design and
development stage, and
c) The responsibilities and authorities for design and development
The organization shall manage the interfaces between different groups involved in design and
development to ensure effective communication and clear assignment of responsibility.
Planning output shall be updated, as appropriate, as the design and development progresses.
GMP Annex
7.3.2 Design and development inputs
Inputs relating to product requirements shall be determined and records maintained. These
inputs shall include
a) Functional and performance requirements
b) Applicable statutory and regulatory requirements
c) Where applicable, information derived from previous similar designs, and
d) Other requirements essential for design and development
The inputs shall be reviewed for adequacy. Requirements shall be complete, unambiguous
and not in conflict with each other.
GMP Annex
7.3.3 Design and development outputs
The outputs of design and development shall be in a form suitable for verification against the
design and development input and shall be approved prior to use.
Design and development outputs shall
a) Meet the input requirements for design and development
b) Provide appropriate information for purchasing, production and service provision,
c) Contain or reference product acceptance criteria, and
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d) Specify the characteristics of the product that are essential for its safe and proper use.
GMP Annex
7.3.4 Design and development review
At suitable stages, systematic reviews of design and development shall be performed in
accordance with planned arrangements
a) To evaluate the ability of the results of design and development to meet requirements,
and
b) To identify and problems and propose necessary actions.
Participants in such reviews shall include representatives of functions concerned with the
design and development stage(s) being reviewed. Records of the results of the reviews and
any necessary actions shall be maintained.
GMP Annex
7.3.5 Design and development verification
Verification shall be performed in accordance with planned arrangements to ensure that the
design and development outputs have met the design and development input requirements.
Records of the results of the verification and any necessary actions shall be maintained.
GMP Annex
7.3.6 Design and development validation
Design and development validation shall be performed in accordance with planned
arrangements to ensure that the resulting product is capable of meeting the requirements for
the specified application of intended use, where known. Wherever practicable, validation shall
be completed prior to delivery or implementation of the product. Records of the results of
validation and any necessary actions shall be maintained.
GMP Annex
7.3.7 Control of design and development changes
Design and development changes shall be identified and records maintained. The changes
shall be reviewed, verified and validated, as appropriate, and approved before
implementation. The review of design and development changes shall include evaluation of
the effect of the changes on constituent parts and product already delivered. Records of the
results of the review of the changes and any necessary actions shall be maintained.
GMP Annex
IPEC-PQG:
ISO 9001 includes requirements for ensuring control over design and development activities.
Companies involved in such activities are recommended to follow the requirements of ISO
9001. Full GMP is not always applicable during the design and development of new
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excipients and/or manufacturing processes. However, development batches of excipients that
are intended for use in drug products should be manufactured in accordance with the
applicable provisions of this Guide.
ICH Q10
IV.A. Life Stage Goals
1. Pharmaceutical Development (3.1.1)
The goal of pharmaceutical development activities is to design a product and its
manufacturing process to consistently deliver the intended performance and meet the
needs of patients and healthcare professionals, and regulatory authorities and internal
customers requirements. Approaches to pharmaceutical development are described in
ICH Q8. The results of exploratory and clinical development studies, while outside the
scope of this guidance, are inputs to pharmaceutical development.
2. Technology Transfer (3.1.2)
The goal of technology transfer activities is to transfer product and process knowledge
between development and manufacturing, and within or between manufacturing sites to
achieve product realization. This knowledge forms the basis for the manufacturing
process, control strategy, process validation approach, and ongoing continual
improvement.
7.4 Purchasing
ISO 9001:
7.4.1 Purchasing Process
The organization shall ensure that purchased product conforms to specified purchase
requirements. The type and extent of control applied to the supplier and the purchased
product shall be dependent upon the effect of the purchased product on subsequent product
realization or final product.
The organization shall evaluate and select suppliers based on their ability to supply product in
accordance with the organizations requirements. Criteria for selection, evaluation and reevaluation shall be established. Records of the results of evaluations and any necessary
actions arising from the evaluation shall be maintained.
GMP Annex
Suppliers of quality critical materials and services shall be approved by the Quality Unit after
an evaluation of the suppliers quality management system, including adequate evidence that
they can consistently meet agreed requirements.
The organization shall require that contract manufacturers or laboratories adhere to the
relevant sections of this Annex. (See 4.1)
7.4.2 Purchasing Information
Purchasing information shall describe the product to be purchased, including , where
appropriate,
a) Requirements for approval of product, procedures, processes and equipment
b) Requirements for qualification of personnel
c) Quality management system requirements
The organization shall ensure the adequacy of specified purchase requirements prior to their
communication to the supplier.
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GMP Annex
The organization shall ensure that it is notified of any significant changes to materials that
may potentially impact excipient quality.
7.4.3 Verification of Purchased Product
The organization shall establish and implement the inspection or other activities necessary for
ensuring that purchased product meets specified purchase requirements.
Where the organization or its customer intends to perform verification at the suppliers
premises, the organization shall state the intended verification arrangements and method of
product release in the purchasing information.
GMP Annex
Incoming quality critical materials (including pre-printed labels) shall be physically or
administratively quarantined until they have been tested or otherwise verified and approved
for use. Where quarantine is not feasible, e.g. for materials supplied via pipelines, the
excipient manufacturer shall establish an agreement with the supplier so that they are notified
of material that does not meet specification.
Sampling shall be conducted in accordance with a documented procedure designed to
prevent contamination and cross-contamination.
At least one analytical test shall be conducted to verify the identity of each delivered batch of
raw material, unless they are hazardous or highly toxic or otherwise cannot be sampled.
Materials which are not sampled shall have alternative controls in place to assure their
quality.
Bulk deliveries shall have additional controls to assure freedom from contamination.
Processes to verify the purchased product shall be documented.
IPEC-PQG:
7.4 Purchasing
7.4.1 Purchasing Process
Excipient manufacturers should have a system for selecting and approving suppliers
of quality-critical materials and services (for example subcontract manufacturers and
laboratories). Supplier approval by the quality unit should require an evaluation of the
suppliers quality management system, including adequate evidence that they can
consistently meet agreed requirements. This may require periodic audits of the
suppliers manufacturing facility. Records of these activities should be maintained.
7.4.2
Materials should be purchased against an agreed specification from approved

suppliers.
Purchasing Information
Purchasing agreements should describe the material or service ordered including,
where critical to excipient quality, the following:
the name, type, class, style, grade, item code number or other precise
identification traceable to the raw material and packaging specifications,
drawings, process requirements, inspection instructions and other relevant
technical data, including requirements for approval or qualification of product,
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7.4.3
procedures, process equipment and personnel,

adherence to the appropriate sections of this Guide for relevant contract
manufacturers or laboratories,
a statement to notify the excipient manufacturer of significant changes in qualitycritical raw materials.
Verification of Purchased Product

There should be procedures for the approval and release of quality-critical material.
Upon receipt, quality-critical materials should be placed in quarantine and should not
be used prior to acceptance. Effective quarantine can be established with suitable
identifying labels, signs and/or other manual documentation systems. When
quarantine and stock control are managed with computer systems in lieu of a physical
stock control, then system controls should prevent the use of unreleased material.
Quarantine may not be feasible for materials supplied via pipelines. In these cases
the excipient manufacturer should establish an agreement with the supplier so that
they are notified of material that does not meet specification.
Sampling activities should be conducted under defined conditions, in accordance with
a defined sampling method and using procedures designed to prevent contamination
and cross-contamination.
Quality-critical materials used in the manufacture of an excipient should be tested or
otherwise verified prior to use. Verification should include availability and a check of
the supplier certificate of analysis and, wherever feasible, at least an identification
test. Testing schedules should be organised to separate those tests that are routine
from those that are performed infrequently or only for new suppliers.
Bulk deliveries should have additional controls to assure material purity and freedom
from contamination (for example dedicated tankers, tamper-evident seals, a certificate
of cleaning, analytical testing and/or audit of the supplier).
These procedures, activities and results should be documented.

ICH Q10
7.4 Purchasing
III. Management Responsibility
G. Management of Outsourced Activities and Purchased Materials (2.7)
The pharmaceutical quality system, including the management responsibilities described in
this section, extends to the control and review of any outsourced activities and quality of
purchased materials. The pharmaceutical company is ultimately responsible to ensure
processes are in place to assure the control of outsourced activities and quality of purchased
materials. These processes should incorporate quality risk management and include:
(a) Assessing prior to outsourcing operations or selecting material suppliers, the suitability
and competence of the other party to carry out the activity or provide the material
using a defined supply chain (e.g., audits, material evaluations, qualification).
(b) Defining the responsibilities and communication processes for quality-related activities
of the involved parties. For outsourced activities, this should be included in a written
agreement between the contract giver and contract acceptor.
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(c) Monitoring and review of the performance of the contract acceptor or the quality of the
material from the provider, and the identification and implementation of any essential
improvements.
(d) Monitoring incoming ingredients and materials to ensure they are from approved
sources using the agreed supply chain.
7.5 Production and Service Provision
ISO 9001:
7.5.1 Control of production and service provision
The organization shall plan and carry out production and service provision under
controlled conditions. Controlled conditions shall include, as applicable,
a) The availability of information that describes the characteristics of the product,
b) The availability of work instructions, as necessary,
c) The use of suitable equipment,
d) The availability and use of monitoring and measuring equipment
e) The implementation of monitoring and measurement, and
f) The implementation of product release, delivery and post-delivery activities.
GMP Annex
Controlled conditions shall include, as applicable:
a) The availability of information that specifies the characteristics of the product.
b) The availability of work instructions, as necessary
For batch processes an accurate reproduction of the appropriate master
production instructions shall be issued to the production area. For continuous
processes, there shall be a defined process and records shall be available.
Records for both batch and continuous processing, where critical to excipient quality
shall include:
date/time each step was completed or date/time log of key parameters,

identification of persons performing and directly supervising or checking each
significant step, operation or control parameter,
identification of major equipment and lines used,
cleaning of equipment and utensils
conformance to specified operating ranges,
material inputs to enable traceability, for example batch number and quantities
of raw material/intermediate, time it was added, etc,
description of sampling performed,
in-process and laboratory control results,
labelling control records
failures, deviation and their investigations, and
results of final product inspection.
and as applicable:
the quantity produced for the defined batch and a statement of the percentage
of theoretical yield,
inspection of the packaging and labelling area before and after use, labelling
control records to ensure the correct label is applied to all containers,
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Records of quality-critical equipment use shall allow the sequence of cleaning,
maintenance and production activities to be determined. Where multi-purpose
equipment is in use records shall identify the previous usage.
Packaging and labelling controls shall be documented and shall ensure:
the correct label is applied to all containers.
correct labels are printed and issued containing the correct information
excess labels are immediately destroyed or returned to controlled storage
packaging and labelling facilities are inspected immediately before use to
ensure that materials that are not required for the current operation have been
removed
Where solvents are recovered and reused in same process or different process they
shall meet appropriate specifications prior to reuse or mixing with other approved
material.
The use of mother liquors or filtrates containing recoverable amounts of excipient,
reactants or intermediates shall be documented and records maintained to enable
traceability.
c) the use of suitable equipment,
The manufacturer shall design and justify equipment cleaning and sanitization
procedures and provide evidence of their effectiveness.
Equipment and utensils shall be cleaned, and sanitised where critical to excipient
quality. The cleaning status of equipment shall be identified.
For continuous processing the frequency of equipment cleaning shall be determined by
the manufacturer and justified.
d) The availability and use of monitoring and measuring equipment
e) The implementation of monitoring and measurement,
In process sampling methods shall be documented. Sampling methods shall define the
time and location of sampling, and shall ensure that the sample is representative and
clearly labelled. In-process samples shall not be returned to production for
incorporation into the final batch.
f)
The implementation of product release, delivery and post-delivery activities

7.5.2 Validation of processes for production and service provision

The organization shall validate any processes for production and service provision where the
resulting output cannot be verified by subsequent monitoring or measurement and, as a
consequence, deficiencies become apparent only after the product is in use or the service
has been delivered.
Validation shall demonstrate the ability of these processes to achieve planned results.
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The organization shall establish arrangements for these processes including , as applicable,
a) defined criteria for review and approval of the processes,
b) approval of equipment and qualification of personnel
c) use of specific methods and procedures
d) requirements for records
e) revalidation
GMP Annex
The consistent operation of the Excipient manufacturing process shall be demonstrated.
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.
7.5.3 Identification and traceability
Where appropriate, the organization shall identify the product by suitable means throughout
product realization.
The organization shall identify the product status with respect to monitoring and measurement
requirements throughout product realization.
Where traceability is a requirement, the organization shall control the unique identification of
the product and maintain records.
GMP Annex
Identification and traceability are specified requirements for quality critical raw
materials, packaging materials, intermediates and finished excipients. Records shall
allow traceability of the excipient from raw materials through delivery to initial
customers. The methods used for traceability and identification of raw materials used in
excipients produced by continuous processing shall be defined.
Excipient labels shall include:
a) the name of the excipient and grade if applicable,
b) the organisations name,
c) the batch number, and
d) any special storage conditions, if applicable.
7.5.4 Customer property
The organization shall exercise care with customer property while it is under the
organizations control or being used by the organization. The organization shall identify, verify,
protect and safeguard customer property provided for use or incorporation into the product. If
any customer property is lost, damaged or otherwise found to be unsuitable for use, the
organization shall report this to the customer and maintain records.
GMP Annex
7.5.5 Preservation of product
The organization shall preserve the product during internal processing and delivery to the
intended destination in order to maintain conformity to requirements. As applicable,
preservation shall include identification, handling, packaging, storage and protection.
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Preservation shall also apply to the constituent parts of a product.
GMP Annex
Records of storage conditions shall be maintained if they are critical for the maintenance
of raw material, intermediate or excipient quality characteristics. Storage and handling
procedures shall be defined in order to protect containers and closures, minimise the risk
of contamination, damage or deterioration of the excipient and avoid mix-ups.
An excipient packaging system shall include the following features:
a) written packaging specifications,
b) tamper evident seals,
c) where containers are re-used, cleaning procedures including means of removing
previous labels, and
d) containers that do not adversely interact with or contaminate the excipient,
Distribution records shall be retained to enable retrieval of a batch of excipient.
IPEC-PQG:
7.5.1 Control of Production and Service Provision
Production activities should be carried out under controlled conditions (see also
section 7.1).
Specific examples of important controls, some of which may not be applicable to all
excipient manufacturers, are illustrated in the following sections.
7.5.1.1 Production Instructions and Records
Production instructions and records are required but may differ for the type of
operation, for example batch versus continuous processes.
There should be a controlled document that describes how the excipient is
produced (for example master production instructions, master production and
control records, process definitions etc.).
For batch processes an accurate reproduction of the appropriate master
production instructions should be issued to the production area. For continuous
processes a current processing log should be available.
Records should be available for each batch of excipient produced and should
include complete information relating to the production and control of each batch.
For continuous processes the batch and its records should be defined (for
example based on time or defined quantity). Records may be in different locations
but should be readily retrievable.
Records for both batch and continuous processing, where critical to excipient
quality, should include:
date/time each step was completed or date/time log of key parameters,
identification of persons performing and directly supervising or checking
each significant step, operation or control parameter,
identification of major equipment and lines used,
material inputs to enable traceability, for example batch number and
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quantities of raw material/intermediate, time it was added, etc.,

in-process and laboratory control results,
the quantity produced for the defined batch and a statement of the
percentage of theoretical yield, unless not quantifiable (for example as in
some continuous processes),
inspection of the packaging and labelling area before and after use,
labelling control records,
description of excipient product containers and closures,
description of sampling performed,
failures, deviation and their investigations,
results of final product inspection.
7.5.1.2 Equipment Cleaning

The manufacturer should design and justify cleaning and sanitisation procedures
and provide evidence of their effectiveness. In multi-purpose plants the use of the
model product approach (groups of product of similar type) may be used in
justifying a suitable procedure.
Cleaning and sanitisation procedures should be documented. They should contain
sufficient detail to allow operators to clean each type of equipment in a
reproducible and effective manner. There should be a record confirming that these
procedures have been followed.
Equipment and utensils should be cleaned and sanitised where critical to excipient
quality and at appropriate intervals to prevent contamination and crosscontamination of the excipient. The cleaning status of equipment should be
recorded appropriately.
Where multi-purpose equipment is in use it is important to be able to determine
previous usage when investigating cross-contamination or the possibility of such
contamination (see also 7.5.1.7).
During a production campaign incidental carry-over frequently occurs and is
acceptable usually since clean-up between successive batches of the same
excipient is not normally required to maintain quality levels. Products that leave
residues that cannot be effectively removed should be produced in dedicated
equipment.
For continuous processing the frequency of equipment cleaning should be
determined by the manufacturer and justified.
7.5.1.3 Recovery of Solvents, Mother Liquors and Second Crop Crystallisations
Where solvents are recovered and reused in the same process or different
processes they should meet appropriate standards prior to reuse or mixing with
other approved material.
Mother liquors or filtrates containing recoverable amounts of excipient, reactants
or intermediates are frequently reused. Such processes should be documented in
the production records or logs to enable traceability.
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7.5.1.4 In-process Blending or Mixing
In process blending or mixing to assure batch uniformity or to facilitate processing
should be controlled and documented. If the intent of the operation is to ensure
batch uniformity it should be performed so as to assure homogenous mixing of
materials to the extent feasible and should be reproducible from batch to batch.
7.5.1.5 In-process Control
In-process inspection and testing should be performed based upon monitoring the
process or actual sample analysis at defined locations and times. Sampling
methods should be documented to ensure that the sample is representative and
clearly labelled.
In-process samples should not be returned to production for incorporation into the
final batch.
The results of in-process tests should be recorded and should conform to
established process parameters or acceptable tolerances. Work instructions
should define the procedure to follow and how to utilise the inspection and test
data to control the process. There should be defined actions to be taken when the
results are outside specified limits.
Where approval to continue with the process is issued within the production
department, the specified tests should be performed by trained personnel and the
results recorded.
7.5.1.6 Packaging and Labelling
Procedures should be employed to protect the quality and purity of the excipient
when it is packaged and to assure that the correct label is applied to all
containers. Packaging and labelling operations should be designed to prevent
mix-ups.
Procedures should be implemented to ensure that the correct labels are printed
and issued and that the labels contain the correct information. The procedure
should also specify that excess labels are immediately destroyed or returned to
controlled storage. Excess labels bearing batch numbers should be destroyed.
Packaging and labelling facilities should be inspected immediately before use to
ensure that materials that are not required for the next packaging operation have
been removed.
Where excipients are labelled on the packaging line, packaged in pre-printed bags
or bulk-shipped in tank cars there should be documentation of the system used to
satisfy the intent of the above procedures.
7.5.1.7 Records of Equipment Use
Records of quality-critical equipment use should be retained. These records
should allow the sequence of cleaning, maintenance and production activities to
be determined.
7.5.2
Validation of Processes for Production and Service Provision
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An important factor in the assurance of product quality includes the adequate design
and control of the manufacturing process because product testing alone is not
sufficient to reveal variations that may have occurred. Each step of the manufacturing
process should be controlled to the extent necessary to ensure that the excipient
meets established specifications.
The concept of process validation is a key element in ensuring that these quality
assurance goals are met. The process reactions, operating parameters, purification
steps, impurities and key tests needed for process control should be documented,
thus providing the basis for validation.
The full validation program that is typically performed in the pharmaceutical industry
may not always be carried out by the excipient manufacturer. However, the excipient
manufacturer should demonstrate the consistent operation of each manufacturing
process, for example through process capability studies, development and scale-up
reports etc.
7.5.3
Identification and Traceability

7.5.3.1 Traceability
Quality-critical items, for example raw materials, packaging materials,
intermediates and finished excipients should be clearly identified and traceable
through records. These records should allow traceability of the excipient both
upstream and downstream. Identification of raw materials used in batch
production processes should be traceable through the batch numbering
system or other appropriate system. Identification of raw materials used in
excipients produced by continuous processing should indicate the timeframe
during which a particular batch of raw material was processed through the
plant.
Raw materials, including solvents, are sometimes stored in bulk tanks or other
large containers, making precise separation of batches difficult. Nevertheless,
the use of such materials should be documented in production records.
7.5.3.2 Inspection and Test Status
There should be a system to identify the inspection status of quality-critical
items including raw materials, packaging materials, intermediates and finished
excipients. Whilst storing materials in identified locations is preferred, any
means that clearly identifies the test status is satisfactory. Continuously-fed
materials may need special consideration in order to satisfy these
requirements.
7.5.3.3 Labelling
Labelling for excipient packages is subject to national and international
regulatory requirements, which may include transportation and safety
measures. As a minimum, labels should include:
the name of the excipient and grade if applicable,
the excipient manufacturers and/or distributors name,
the batch number from which the complete batch history can be
determined,
special storage conditions, if applicable.
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7.5.4
Customer Property
The excipient manufacturer should establish and maintain procedures for verification,
storage and maintenance of customer-supplied materials intended for incorporation
into the customer's excipient. Verification by the manufacturer does not relieve the
customer of the responsibility to provide an acceptable material. Material that is lost
damaged or is otherwise unsuitable for use should be recorded and reported to the
customer. In this case, procedures should be in place for acceptable disposition and
replacement of the material. The manufacturer should also make provisions to protect
other real and intellectual property that is provided by the customer (for example test
equipment, test methods and specifications).
7.5.5
Preservation of Product
7.5.5.1 Handling, Storage and Preservation
Excipients, intermediates and raw materials should be handled and stored
under appropriate conditions of temperature, humidity and light so that their
identity, quality and purity are not affected. Outdoor storage of raw materials
(for example acids, other corrosive substances or explosive materials) or
excipients is acceptable provided the containers give suitable protection
against deterioration or contamination of their contents, identifying labels
remain legible and containers are adequately cleaned prior to opening and
use.
Records of storage conditions should be maintained if they are critical for the
continuing conformance of the material to specification.
7.5.5.2 Packaging Systems
An excipient packaging system should include the following features:
documented specifications and examination or testing methods,
cleaning procedures where containers are reused,
tamper-evident seals,
containers that provide adequate protection against deterioration or
contamination of the excipient during transportation and recommended
storage,
containers that do not interact with or contaminate the excipient,
storage and handling procedures which protect containers and closures
and minimise the risk of contamination, damage or deterioration and
which will avoid mix-ups (for example between containers that have
different specifications but are similar in appearance).
If returnable excipient containers are re-used, previous labelling should be
removed or defaced. If the containers are repetitively used solely for the same
excipient, previous batch numbers or the entire label should be removed or
completely obliterated.
7.5.5.3 Delivery and Distribution
Identification and traceability of quality-critical aspects are required of excipient
manufacturers. Distribution records of excipient shipments should be kept.
These records should identify, by excipient batch, where and to whom the
excipient was shipped, the amount shipped and the date of shipment so as to
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facilitate retrieval if necessary. Where excipients are handled by a series of
different distributors, it should be possible to trace them back to the original
manufacturer and not just to the previous supplier.
The manufacturer should maintain the integrity and the quality of the product
after final inspection and test. Where contractually specified, this protection
should be extended to include delivery to the final destination. Excipients
should only be supplied within their expiry and/or retest period.
ICH Q10
IV.A. Life Stage Goals
3. Commercial Manufacturing (3.1.3)
The goals of manufacturing activities include achieving product realization, establishing
and maintaining a state of control, and facilitating continual improvement. The
pharmaceutical quality system should assure that the desired product quality is routinely
met, suitable process performance is achieved, the set of controls are appropriate,
improvement opportunities are identified and evaluated, and the body of knowledge is
continually expanded.
7.6 Control of Monitoring and Measuring Equipment
ISO 9001:
The organization shall determine the monitoring and measurement to be undertaken and the
monitoring and measuring equipment needed to provide evidence of conformity of product to
determined requirements.
The organization shall establish processes to ensure that monitoring and measurement can
be carried out and are carried out in a manner that is consistent with the monitoring and
measurement requirements.
Where necessary to ensure valid results, measuring equipment shall
a) be calibrated or verified, or both, at specified intervals, or prior to use, against
measurement standards traceable to international or national measurement
standards; where no such standards exist, the basis used for calibration or verification
shall be recorded;
b) be adjusted or re-adjusted, as necessary
c) have identification in order to determine its calibration status;
d) be safeguarded from adjustment that would invalidate the measurement result
e) be protected from damage and deterioration during handling, maintenance and
storage.
In addition, the organization shall assess and record the validity of the previous measuring
results when the equipment is found not to conform to requirements. The organization shall
take appropriate action on the equipment and any product affected.
Records of the results of calibration and verification shall be maintained.
When used in the monitoring and measurement of specified requirements, the ability of
computer software to satisfy the intended application shall be confirmed. This shall be
undertaken prior to initial use and reconfirmed as necessary.
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GMP Annex
IPEC-PQG:
7.6 Control of Measuring and Monitoring Devices
Measuring and test equipment, including computerised systems, identified as being
quality-critical should be calibrated and maintained. This includes in-process instruments
as well as test equipment used in the laboratory. The control program should include the
standardisation or calibration of instruments and equipment at suitable intervals in
accordance with an established documented program. This program should contain
specific directions, schedules, limits for accuracy and precision and provisions for
remedial action in the event that accuracy and/or precision limits are not met. Calibration
standards should be traceable to recognised national or Compendial standards as
appropriate.
Instruments and equipment not meeting established specifications should not be used
and an investigation should be conducted to determine the validity of the previous results
since the last successful calibration. The current calibration status of quality-critical
equipment should be known and verifiable to users.
ICH Q10
7.6 Control of Monitoring and Measuring Equipment
No Requirement
8
Measurement, Analysis and Improvement
ISO 9001:
8.1 General
The organization shall plan and implement the monitoring, measurement , analysis and
improvement processes needed
a) to demonstrate conformity to product requirements
b) to ensure conformity to the quality management system, and
c) to continually improve the effectiveness of the quality management system.
This shall include determination of applicable methods, including statistical techniques, and
the extent of their use.
GMP Annex
IPEC-PQG:
8.1 General
The organization should 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 Guide.
The organization should evaluate opportunities for improvements through the measurement
and analysis of product and process trends.
ICH Q10
8.1 General
Pharmaceutical companies should plan and execute a system for the monitoring of process
performance and product quality to ensure a state of control is maintained. An effective
monitoring system provides assurance of the continued capability of processes and controls
to produce a product of desired quality and to identify areas for continual improvement. The
process performance and product quality monitoring system should:
(a) Use quality risk management to establish the control strategy. This can include
parameters and attributes related to drug substance and drug product materials and
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components, facility and equipment operating conditions, in-process controls, finished
product specifications, and the associated methods and frequency of monitoring and
control. The control strategy should facilitate timely feedback / feed forward and
appropriate corrective action and preventive action;
(b) Provide the tools for measurement and analysis of parameters and attributes identified
in the control strategy (e.g., data management and statistical tools);
(c) Analyse parameters and attributes identified in the control strategy to verify continued
operation within a state of control;
(d) Identify sources of variation affecting process performance and product quality for
potential continual improvement activities to reduce or control variation;
(e) Include feedback on product quality from both internal and external sources, e.g.,
complaints, product rejections, non-conformances, recalls, deviations, audits and
regulatory inspections and findings;
(f) Provide knowledge to enhance process understanding, enrich the design space
(where established), and enable innovative approaches to process validation.
Table I: Application of Process Performance and Product Quality Monitoring
System throughout the Product Lifecycle
Pharmaceutical
Development
Technology Transfer
Commercial
Manufacturing
Product Discontinuation
Process and product

knowledge generated
and process and product
monitoring conducted
throughout
development can be
used to establish a
control strategy for
manufacturing.
Monitoring during scaleup activities can provide a

preliminary indication of
process performance and
the successful integration
into manufacturing.
Knowledge obtained
during transfer and scale
up activities can be useful
in further developing the
control strategy.
A well-defined system
for process
performance and
product quality
monitoring should be
applied to assure
performance within a
state of control and to
identify improvement
areas.
Once manufacturing
ceases, monitoring such as
stability testing should
continue to completion of
the studies. Appropriate
action on marketed
product should continue
to be executed according
to regional regulations.
8.2 Monitoring and Measurement

ISO 9001:
8.2.1 Customer Satisfaction
As one of the measurements of the performance of the quality management system, the
organization shall monitor information relating to customer perception as to whether the
organization has met customer requirements. The methods for obtaining and using this
information shall be determined.
GMP Annex
8.2.2 Internal audits
The organization shall conduct internal audits at planned intervals to determine whether the
quality management system
a) conforms to the planned arrangements, to the requirements of ISO 9001:2008 and to
the quality management system requirements established by the organization, and
b) is effectively implemented and maintained.
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An audit programme shall be planned, taking into consideration the status and importance of
the processes and areas to be audited, as well as the results of the previous audits. The audit
criteria, scope, frequency and methods shall be defined. The selection of auditors and
conduct of audits shall ensure objectivity and impartiality of the audit process. Auditors shall
not audit their own work.
A documented procedure shall be established to define the responsibilities and requirements
for planning and conducting audits, establishing records and reporting results.
Records of audits and their results shall be maintained.
The management responsibility for the area being audited shall ensure that any necessary
corrections and corrective actions are taken without undue delay to eliminate detected
nonconformities and their causes.
Follow-up activities shall include the verification of the actions taken and the reporting of
verification results.
GMP Annex
8.2.3 Monitoring and measurement of processes
The organization shall apply suitable methods for monitoring and, where applicable,
measurement of the quality management system processes. These methods shall
demonstrate the ability of the processes to achieve planned results. When planned results
are not achieved, correction and corrective action shall be taken, as appropriate.
GMP Annex
The need to notify customers when critical deviations from planned results occur shall be
evaluated (see 7.2.1 and 7.2.3).
8.2.4 Monitoring and measurement product
The organization shall monitor and measure the characteristics of the product to verify that
product requirements have been met. This shall be carried out at appropriate stages of the
product realization process in accordance with the planned arrangements. Evidence of
conformity with the acceptance criteria shall be maintained.
Records shall indicate the person(s) authorizing the release of product for delivery to the
customer.
The release of product and delivery of service to the customer shall not proceed until the
planned arrangements have been satisfactorily completed, unless otherwise approved by a
relevant authority and, where applicable, the customer.
GMP Annex
If the excipient manufacturer claims that their product is in compliance with a
pharmacopoeia or an official compendium, then:
non-compendial analytical tests shall be demonstrated to be at least

equivalent to those in the compendia, and
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the method shall comply with applicable general chapters and notices.
Written procedures shall be established to monitor and control the quality characteristics
of excipients. These shall include, as applicable:
a) laboratory controls; including the preparation and use of laboratory solutions,
reference standards,
i. Laboratory controls shall include complete data derived from tests necessary
to ensure conformance with specifications and standards. Records of these
controls shall include:
identity of the sample,
test method used,
raw data including sample preparation,

calculations performed
test results and how they compare with established specifications, and
person who performed each test and the date(s) the tests were performed.
ii. There shall be a documented procedure and records for the preparation of
laboratory reagents and solutions. Reagents and solutions shall be labelled
with the proper name, concentration and expiry date.
iii. Primary reference reagents and standards shall be verified on receipt and
appropriately stored. There shall be a documented procedure for the
qualification of secondary reference standards against primary reference
standards that includes their preparation, approval and storage. The reevaluation period shall be defined for secondary reference standards and each
batch shall be periodically re-qualified in accordance with a documented
procedure.
b) excipient testing and release,
i. There shall be a procedure to ensure that appropriate manufacturing
documentation, in addition to the test results, is evaluated prior to release of
the finished excipient. The Quality Unit shall be responsible for the release of
the finished excipient.
Note:
For excipients produced by continuous processes assurance that the excipient

conforms to documented specifications may be achieved through the results of
in-process testing or other process control records.
c) investigation of out-of-specification test results,
i. Out-of-specification (OOS) test results shall be investigated and documented
according to a documented procedure.
d) the retention of samples of each batch of the excipient,
i. Where practical, a representative sample of each batch of the excipient shall
be retained. The retention period shall be appropriate to the expiry or reevaluation date. The retained samples shall be stored and maintained in such
a manner that they are readily retrievable in facilities that provide a suitable
environment. The sample size shall be at least twice the amount required to
perform complete specification testing.
e) preparation and issue of certificates of analysis,
f) the tests and limits for impurities,
i. Excipient manufacturers shall identify and set appropriate limits for known
impurities, and
g) an evaluation of excipient stability,
The organization shall evaluate excipient stability based on historic data or specific
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studies. The organization shall define and justify an expiry or retest period and ensure
this is communicated to the customer
IPEC-PQG:
8.2.1 Customer Satisfaction
The excipient manufacturer should establish measurement activities to assess customer
satisfaction. Such measurements can include customer complaints, return of excipients
and customer feedback. This information should drive activities that strive to
continuously improve customer satisfaction.
8.2.2 Internal Audit
The excipient manufacturer should carry out a comprehensive system of planned and
documented internal quality audits. These should determine whether quality activities
comply with planned arrangements and the effectiveness of the quality management
system. Audits should be scheduled on the basis of the status and importance of the
activity. Audits and follow-up actions should be carried out in accordance with
documented procedures.
Audit results should be documented and discussed with management personnel having
responsibility in the area audited. Management personnel responsible for the area
audited should take corrective action on the nonconformities found.
Appendix A, Auditing Considerations will be of assistance in establishing an internal audit
program.
8.2.3 Monitoring and Measurement of Processes
The excipient manufacturer should identify the tests and measurements necessary to
adequately control manufacturing and quality management system processes. Where
critical to excipient quality, techniques that are used to verify that the processes are
under control should be established.
Corrective action should be taken to ensure the excipient meets requirements when
deviations from planned results occur.
Periodic reviews of key indicators such as process quality attributes and process failures
should be conducted to assess the need for improvements.
8.2.4 Monitoring and Measurement of Product
The excipient manufacturer should establish the test methods and procedures to ensure
the product consistently meets specifications.
Analytical methods should be fit for purpose. The analytical methods may be those
included in the current edition of the appropriate pharmacopoeia or another accepted
standard. However, the methods may also be non-compendial.
If the excipient manufacturer claims that their product is in compliance with a
pharmacopoeia or an official compendium, then:
non-compendial analytical tests should be demonstrated to be equivalent to those in

the compendia,
it should comply with applicable general chapters and notices.
8.2.4.1 Laboratory Controls

Laboratory controls should include complete data derived from tests necessary to
ensure conformance with specifications and standards including:
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a description of the sample received for testing together with the material name,
batch number or other distinctive code and date the sample was taken,
a statement referencing each test method used,
a record of raw data secured during each test including graphs, chromatograms,
charts and spectra from laboratory instrumentation, identified to show the specific
material and batch tested,
a record of calculations performed in connection with the test,
test results and how they compare with established specifications,
a record of the person who performed each test and the date(s) the tests were
performed.
There should be a documented procedure for the preparation of laboratory reagents

and solutions. Purchased reagents and solutions should be labeled with the proper
name, concentration and expiry date. Records should be maintained for the
preparation of solutions including the name of the solution, date of preparation and
quantities of material used.
Volumetric solutions should be standardized according to an internal method or by
using a recognized standard. Records of the standardization should be maintained.
Where used, primary reference reagents and standards should be appropriately
stored and need not be tested upon receipt provided that a certificate of analysis from
the supplier is available. Secondary reference standards should be appropriately
prepared, identified, tested, approved and stored. There should be a documented
procedure for the qualification of secondary reference standards against primary
reference standards.
The re-evaluation period should be defined for secondary reference standards and
each batch should be periodically re-qualified in accordance with a documented
protocol or procedure.
8.2.4.2 Finished Excipient Testing and Release
Finished excipient testing should be performed on each batch to ensure that the
excipient conforms to documented specifications. There should be a procedure to
ensure that appropriate manufacturing documentation, in addition to the test results, is
evaluated prior to release of the finished excipient. The quality unit should be
responsible for the release of the finished excipient.
For excipients produced by continuous processes assurance that the excipient
conforms to documented specifications may be achieved through the results of inprocess testing or other process control records.
8.2.4.3 Out-of-Specification Test Results
Out-of-specification (OOS) test results should be investigated and documented
according to a documented procedure.
Retest sample results may only be used to replace the original test result if it is
demonstrated that the original result is erroneous based on a documented
investigation.
When statistical analysis is used both the original and retest data must be included.
The OOS procedure should define which statistical techniques are to be used and
under what circumstances.
These same principles apply when the sample is suspected of not being
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representative of the material from which it was taken.
8.2.4.4 Retained Samples
Where practical, a representative sample of each batch of the excipient should be
retained. The retention period should be appropriate to the expiry or re-evaluation
date. The retained samples should be stored and maintained in such a manner that
they are readily retrievable in facilities that provide a suitable environment. The
sample size should be at least twice the amount required to perform complete
specification testing.
8.2.4.5 Certificates of Analysis
The organization should provide certificates of analysis to the required specification
for each batch of excipient. More details on the suitable contents of a certificate of
analysis can be found in the IPEC-Americas Certificate of Analysis Guide for Bulk
Pharmaceutical Excipients and the UK Guidance on Certificates of Analysis from The
Rules and Guidance for Pharmaceutical Manufacturers and Distributors.
8.2.4.6 Impurities
Where possible, excipient manufacturers should identify and set appropriate limits for
impurities. The limits should be based upon appropriate safety data, limits as
described in official compendia or other requirements and sound GMP considerations.
Manufacturing processes should be adequately controlled so that the impurities do not
exceed such established limits.
Many excipients are extracted from or purified using organic solvents.
These solvents are normally removed by drying. It is important that excipient
specifications include tests and limits for solvent residues.
8.2.4.7 Stability
While many excipient products are stable and may not require extensive testing to
assure stability, the stability of excipients is an important factor contributing to the
overall quality of the drug product. For excipients that have been on the market for a
long time historical data may be used to indicate stability.
Where historical data do not exist a documented testing and/or evaluation program
designed to assess the stability characteristics of the excipient should be undertaken.
The results of such stability testing and/or evaluation should be used in determining
appropriate storage conditions and retest or expiry dates. The testing program should
include the following:
the number of batches, sample sizes and test intervals,

storage conditions for samples retained for testing,
suitable stability-indicating test methods,
storage of the excipient in containers that simulate the market container, where
possible.
The stability of excipients may be affected by undetected changes in raw materials or

subtle changes in manufacturing procedures or storage conditions. Excipients may
also be shipped in a variety of packaging types that can affect their stability (for
example, plastic or glass bottles, metal or plastic drums, bags, tank cars or other bulk
containers, etc.).
Some excipients may be available in different grades (for example, various molecular
weights of a polymer or different monomer ratios, different particle sizes, bulk
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densities etc.) or may be mixtures of other excipients. These excipients may be very
similar to others within a product group. Minor quantitative differences of some of the
components may be the only significant variation from one product to another. For
these types of excipients, a model product approach may be appropriate to assess
the stability of similar excipients. Stability studies of this type should involve selection
of several model products that would be expected to simulate the stability of the
product group being assessed.
This selection should be scientifically sound and documented. Data from stability
studies of these model products can be used to determine theoretical stability for
similar products.
8.2.4.8 Expiry/Retest Periods
An expiry or retest period should be assigned to each excipient and communicated to
the customer. Common practice is to use a retest period, rather than an expiry period.
ICH Q10
No requirement
8.3 Control of Nonconforming Product
ISO 9001:
The organization shall ensure that product which does not conform to product requirements is
identified and controlled to prevent its unintended use or delivery. A documented procedure
shall be established to define the controls and related responsibilities and authorities for
dealing with non-conforming product.
Where applicable, the organization shall deal with nonconforming product by one or more of
the following ways;
a) By taking action to eliminate the detected non-conformity
b) By authorizing its use, release or acceptance under concession by a relevant authority
and, where applicable, by the customer:
c) By taking action to preclude its original intended use or application;
d) By taking action appropriate to the effects, or potential effects, of the nonconformity
when nonconforming product is detected after delivery or use has started;
When nonconforming product is corrected it shall be subject to re-verification to demonstrate
conformity to the requirements.
Records of the nature of nonconformities and any subsequent actions taken, including
concessions obtained, shall be maintained.
GMP Annex
e) Reprocessing shall only occur when it has already been documented that the
excipient may be manufactured in that manner, and
f) Reworking shall only occur after the Quality Unit has documented a review of the risk
to excipient quality.
As applicable, when performing the risk assessment, consideration shall be given to:
new impurities that may be introduced as a result of reworking,
additional testing to control the reworking,
records and traceability to the original batches,
suitable acceptance criteria for the reworked excipient,
impact on stability or the validity of the re-evaluation interval, and
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performance of the excipient
notifying the authorities where the product has been registered
Records of reprocessing and reworking activities shall be retained.
There shall be a procedure defining how to manage the retrieval of an excipient.
Returned excipients shall be identified as such and quarantined until an evaluation of
their quality has been completed by the Quality Unit(s). Records shall include the
reason for return and the decision made as to the final disposition.
IPEC-PQG:
Raw material, intermediate or finished excipient found not to meet its specification should be
clearly identified and controlled to prevent inadvertent use or release for sale. A record of
nonconforming product should be maintained. Incidences of non-conformance should be
investigated to identify the cause. The investigation should be documented and action taken
to prevent recurrence.
There should be a documented procedure defining how the retrieval of an excipient from
distribution should be conducted and recorded.
Procedures should exist for the evaluation and subsequent disposition of nonconforming
products. Nonconforming product should be reviewed in accordance with documented
procedures to determine if it may be:
reprocessed/reworked to meet the specified requirements,

accepted by the customer with their agreement,
re-graded for other applications,
destroyed.
8.3.1 Reprocessing
Repetition of an activity that is a normal part of the manufacturing process (reprocessing)
should only occur when it has already been documented that the excipient may be made
in that manner. In all other cases, the guidance for reworking should be followed.
8.3.2 Reworking
An activity that is not a normal part of the manufacturing process (reworking) should only
be conducted following a documented review of risk to excipient quality and approval by
the quality unit. As appropriate, when performing the risk assessment, consideration
should be given to:
new impurities that may be introduced as a result of reworking,

additional testing to control the reworking,
records and traceability to the original batches,
suitable acceptance criteria for the reworked excipient,
impact on stability or the validity of the re-evaluation interval,
performance of the excipient.
When the need to rework an excipient is identified an investigation and evaluation of the
cause is required.
The equivalence of the quality of reworked material to original material should also be
evaluated and documented to ensure that the batch will conform to established
specifications and characteristics.
Batches of excipients that do not conform to specifications individually must not be
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blended with other batches that do conform in an attempt to hide adulterated or substandard material.
8.3.3 Returned Excipients
Returned excipients should be identified and quarantined until the quality unit has
completed an evaluation of their quality. There should be procedures for holding, testing
reprocessing or reworking of the returned excipient. Records for returned products
should be maintained and should include the name of the excipient and the batch
number, reason for the return, quantity returned and ultimate disposition of the returned
excipient.
ICH Q10
No requirement
8.4 Analysis of Data
ISO 9001:
The organization shall determine, collect and analyse appropriate data to demonstrate the
suitability and effectiveness of the quality management system and to evaluate where
continual improvement of the effectiveness of the quality management system can be made.
This shall include data generated as a result of monitoring and measurement and from other
relevant sources.
The analysis of data shall provide information relating to
a) customer satisfaction
b) conformity to product requirements
c) characteristics and trends of processes and products, including opportunities for
preventive action
d) suppliers.
GMP Annex
IPEC-PQG:
The excipient manufacturer should develop methods for evaluating the effectiveness of its
quality management system and use those data to identify opportunities for improvement.
Such data can be derived from customer complaints, product reviews, process capability
studies, internal and customer audits. The analysis of such data may be used as part of the
management review (see also 5.6).
A periodic review of key indicators such as product quality attributes, customer complaints
and product nonconformities may be conducted to assess the need for improvements
ICH Q10
No requirement
8.5 Improvement
ISO 9001:
8.5.1 Continual Improvement
The organization shall continually improve the effectiveness of the quality management
system through the use of the quality policy, quality objectives, audit results, analysis of data,
corrective and preventive actions and management review.
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GMP Annex
8.5.2 Corrective action
The organization shall take action to eliminate the causes of nonconformities in order to
prevent recurrence. Corrective actions shall be appropriate to the effects of the
nonconformities encountered.
A documented procedure shall be established to define the requirements for
a) reviewing nonconformities (including customer complaints)
b) determining the causes of nonconformities
c) evaluating the need action to ensure that nonconformities do not recur
d) determining and implementing action needed
e) records of the results of action taken
f) reviewing the effectiveness of the corrective action taken
GMP Annex
Investigations shall extend to other batches that may have been associated with the
nonconformity
8.5.3 Preventative action
The organization shall determine action to eliminate the causes of potential nonconformities
in order to prevent their occurrence. Preventive actions shall be appropriate to the effects of
the potential problems.
A documented procedure shall be established to define requirements for
a) determining potential nonconformities and their causes
b) evaluating the need for action to prevent occurrences of nonconformities
c) determining and implementing action needed
d) records of results of action taken
e) reviewing the effectiveness of preventive action taken.
GMP Annex
IPEC-PQG:
8.5 Improvement
8.5.1 Continual Improvement
The excipient manufacturer should take proactive measures to continuously improve
manufacturing and quality management system processes. To identify opportunities for
continual improvement, analysis of the following performance indicators may be
considered:
causes of nonconforming product,
results of internal and external audits,
customer returns and complaints,
process and operational failures.
8.5.2 Corrective Action
The excipient manufacturer should establish, document and maintain procedures for:
determining the root causes of nonconformities,
ensuring that corrective actions are implemented and effective,
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implementing and recording changes in procedures resulting from corrective

action.
8.5.3 Preventive Action

The excipient manufacturer should establish, document and maintain procedures for:
initiating preventive actions to deal with problems at a level corresponding to the
risks,
implementing and recording changes in procedures resulting from preventive
action.
ICH Q10
8.5 Improvement
3.2.2 Corrective and preventative (CAPA) System
The pharmaceutical company should have a system for implementing corrective actions and
preventive actions resulting from the investigation of complaints, product rejections, nonconformances, recalls, deviations, audits, regulatory inspections and findings, and trends
from process performance and product quality monitoring. A structured approach to the
investigation process should be used with the objective of determining the root cause. The
level of effort, formality, and documentation of the investigation should be commensurate with
the level of risk, in line with ICH Q9. CAPA methodology should result in product and process
improvements and enhanced product and process understanding.
Table II: Application of Corrective Action and Preventive Action System
throughout the Product Lifecycle
Development
Technology
Transfer
Commercial
Manufacturing
Product Discontinuation
Product or process
variability is explored.
CAPA methodology is
useful where corrective
actions and preventive
actions are incorporated into
the iterative design and
development process.
CAPA can be used

as an effective
system for feedback,
feed forward and
continual
improvement.
CAPA should be
used and the
effectiveness of the
actions should be
evaluated.
CAPA should continue after

the product is discontinued.
The impact on product
remaining on the market
should be considered as well
as other products which might
be impacted
3.2.3 Change Management System

Innovation, continual improvement, the outputs of process performance and product quality
monitoring and CAPA drive change. In order to evaluate, approve and implement these
changes properly, a company should have an effective change management system. There is
generally a difference in formality of change management processes prior to the initial
regulatory submission and after submission, where changes to the regulatory filing might be
required under regional requirements.
The change management system ensures continual improvement is undertaken in a timely
and effective manner. It should provide a high degree of assurance there are no unintended
consequences of the change.
The change management system should include the following, as appropriate for the stage of
the lifecycle:
(a) Quality risk management should be utilised to evaluate proposed changes. The level
of effort and formality of the evaluation should be commensurate with the level of risk;
(b) Proposed changes should be evaluated relative to the marketing authorisation,
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including design space, where established, and/or current product and process
understanding. There should be an assessment to determine whether a change to the
regulatory filing is required under regional requirements. As stated in ICH Q8, working
within the design space is not considered a change (from a regulatory filing
perspective). However, from a pharmaceutical quality system standpoint, all changes
should be evaluated by a companys change management system;
(c) Proposed changes should be evaluated by expert teams contributing the appropriate
expertise and knowledge from relevant areas (e.g., Pharmaceutical Development,
Manufacturing, Quality, Regulatory Affairs and Medical), to ensure the change is
technically justified. Prospective evaluation criteria for a proposed change should be
set;
(d) After implementation, an evaluation of the change should be undertaken to confirm
the change objectives were achieved and that there was no deleterious impact on
product quality.
Table III: Application of Change Management System throughout the Product
Lifecycle
Pharmaceutical
Development
Technology Transfer
Commercial
Manufacturing
Product
Discontinuation
Change is an inherent part

of the development process
and should be documented;
the formality of the change
management process should
be consistent with the stage
of pharmaceutical
development.
The change
management system
should provide
management and
documentation of
adjustments made to
the process during
technology transfer
activities.
A formal change
management system
should be in place for
commercial
manufacturing. Oversight
by the quality unit should
provide assurance of
appropriate science and
risk based assessments.
Any changes after

product
discontinuation should
go through an
appropriate change
management system

Quality System Comparison - Completed

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Quality Management System Comparison

Design and Content Considerations

A Quality Manual or equivalent documentation approach should be established and should

developing and implementing an internal audit program.

Complaint, deviation, CAPA and change management processes;

Materials should be purchased against an agreed specification from approved

procedures, process equipment and personnel,

Verification of Purchased Product

These procedures, activities and results should be documented.

date/time each step was completed or date/time log of key parameters,

The implementation of product release, delivery and post-delivery activities

7.5.2 Validation of processes for production and service provision

quantities of raw material/intermediate, time it was added, etc.,

7.5.1.2 Equipment Cleaning

Validation of Processes for Production and Service Provision

Identification and Traceability

Process and product

Monitoring during scaleup activities can provide a

8.2 Monitoring and Measurement

non-compendial analytical tests shall be demonstrated to be at least

identity of the sample,

test method used,

raw data including sample preparation,

For excipients produced by continuous processes assurance that the excipient

non-compendial analytical tests should be demonstrated to be equivalent to those in

8.2.4.1 Laboratory Controls

There should be a documented procedure for the preparation of laboratory reagents

the number of batches, sample sizes and test intervals,

The stability of excipients may be affected by undetected changes in raw materials or

reprocessed/reworked to meet the specified requirements,

new impurities that may be introduced as a result of reworking,

implementing and recording changes in procedures resulting from corrective

8.5.3 Preventive Action

CAPA can be used

CAPA should continue after

3.2.3 Change Management System

Change is an inherent part

Any changes after

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