Prepared by: Jaya Krishna Gude

M.S. (Pharm.), NIPER.

 S. No Table of Contents Page No.
1 Why Validation is Needed?? 3
2 GAMP5 4
3 Validation Deliverables 7
4 European Union – Drug Approval Process 9
5 Annex 11-Computerized Systems 13
6 Difference between EU Annex-11 and 21 CFR Part 11 15
7 ISO 15
8 Medical Devices 16
9 21 CFR Part 820: Quality System Regulation 18
10 Definitions: Medical Devices and Quality Control 20

So what's this Document all about?

This Document covers the Importance of Validation in Pharmaceutical Industry, Validation
Approach and the depth of validation need to be done, the steps of the validation process
depending on the category described in GAMP5.
And also the European Union Drug Approval Procedure and Annex-11: Computerized
Systems.

It also talks about the Medical Devices and Quality System Regulation (21 CFR Part 820) as
per the US FDA.

Prepared by: Jaya Krishna Gude

M.S. (Pharm.), NIPER.

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 Validation
WHY VALIDATION IS NEEDED???

Currently, in the pharmaceutical manufacturing industry, validation plays a vital role as

Validation is an important requirement imposed by authorities worldwide to regulate the
production of pharmaceutical and medical devices.

One of the major GMP requirements is that all of the critical manufacturing equipment,
utilities, and facilities in the pharmaceutical industries must be properly qualified and
validated prior to production.
The concept of validation was first proposed by Ted Byers and Bud Loftus in the mid-1970s
to improve the quality of pharmaceutical products.

Validation is concerned mainly with processes it is referred to as a qualification when the

same approach is applied to a machine or equipment instead of a process.
Validation involves confirmation by examination and provision of objective evidence that the
particular requirements for a specific intended use are fulfilled.
No pharmaceutical plant is complete without an IT system, which is responsible for controlling,
supporting and documenting various processes. It is extremely important to validate the
computer and IT systems as it makes sure that all the concerned IT applications are fulfilling
their intended purposes.

Computer system validation checks the effectiveness and the efficiency with which the system
is meeting the purpose for which it was designed by analysing crucial aspects such as risk
management and in-depth validation approach.

All new computer systems must be prospectively validated before going into production.
For existing computer systems, concurrent validation may be considered where limited
documentation on the appropriate technology exists, and where an acceptable level of
confidence can be established by reviewing and documenting the operating history.

For existing computer systems, retrospective evaluation is discouraged.

It is extremely difficult to evaluate a computer system retrospectively, being generally costlier
and time consuming than prospective validation. Retrospective evaluation should be used only
as a corrective measure in response to deficiencies noted concerning prior validation efforts.

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GAMP5: Good Automated Manufacturing Practice
GAMP5: A Risk based approach to compliant GxP computerized systems is a reference
guidance document which is published by an industry trade group called International Society
for Pharmaceutical Engineering (ISPE) based on inputs from the pharmaceutical industry
Professionals.
It provides a frame work for the risk-based approach to computer system validation where a
system is evaluated and assigned to a predefined category based on its intended use and
complexity.

This Guide describes an integrated approach to the management, maintenance, and control of
regulated computerized systems. GAMP5 terminology and key concepts are applied to the
Operation Phase.

The depth of validation and the steps of the validation process to be followed will vary
depending on the category of software and the complexity and criticality of the system.

GAMP5 key concepts are:

1. Product and process understanding

2. Life cycle approach within a QMS

3. Scalable life cycle activities
4. Science-based quality risk management

5. Leveraging supplier involvement

System Development Life Cycle (SDLC):

The life cycle for any system consists of four major phases:

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Concept: During the concept phase the regulated company considers opportunities to automate
one or more business processes based upon business and benefits. At this phase, initial
requirements will be developed and potential solutions considered. From an initial
understanding of scope, costs and benefits a decision is made on whether to proceed to the
project phase.

Project: The project phase involves planning, supplier assessment and selection, various levels
of specification, configuration and verification leading to acceptance and release for operation.
Risk management is applied to identify risks and to remove or reduce them to an acceptable
level.

Operation: This phase is the longest phase and is managed by the use of defined, up to date,
operational procedures applied by personnel who have appropriate training, education, and
experience. Maintaining control (Including Security), fitness for intended use and compliance
are key aspects. The management of changes of different impact, scope and complexity is an
important activity during this phase.

Retirement: The final phase is the ultimate retirement of the system. It involves decisions
about data retention, migration or destruction and the management of these processes.

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System documentation and Validation approach depends on the categorization of the
system.
Category 1: Operating Systems
Category 3: Standard / Non-Configured Software
Category 4: Configured Software

Category 5: Customized Software

Difference between GAMP4 and GAMP5:

Category GAMP 4 GAMP 5

Category 1 Operating systems Infrastructure Software

Category 2 Firmware NA

Category 3 Standard software Non-configured products

Category 4 Configured software Configured products

Category 5 Custom software Custom applications

 Operating systems (e.g., Windows)

 Standard instruments (e.g., bar code readers, some laboratory instruments)
 Standard software packages (e.g., spreadsheets, databases)
 Configurable software packages, (e.g., LIMS, SCADA, building automation systems)
 Custom-built systems (e.g., automated process control systems)

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 Computer System Validation Documentation flow:
System Classification Assessment
Validation Plan
User Requirement Specification
System Requirement Specification
Functional Risk Assessment
Design Specification
Configuration Specification
Installation Qualification
Operational Qualification
Performance Qualification
Requirement Traceability Matrix
Validation Summary Report
System Release / Software Release
System Retirement
System Decommissioning Report

Validation Deliverables based on Software Category:

Validation Deliverables

Software
FS/FRS

CS/DS

Category
RTM
FRA

VSR
URS
IRA

OQ

PQ
VP
SA

IQ

Category 1   - - - - -  - - - -

Category 3   -  - - -     

Category 4            

Category 5            

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 Personnel Responsible for Validation Deliverables:

Validation
Prepared Reviewer(s) Approver(s)
Deliverable
Planning

Initial Risk System Owner/ System Owner,

QA
Assessment Validation Team Process Owner

Supplier assessment QA QA QA

Project System Owner,

Validation plan Manager/Validation QA
Team Process Owner, SME

Specification

User Requirements System Owner/ System Owner,

QA
Specification Validation Team Process Owner, SME

Functional System Owner,

Vendor QA
Specification Process Owner, SME

Configuration System Owner,

Vendor QA
Specification Process Owner, SME

System Owner,
Design Specification Vendor QA
Process Owner, SME

Functional Risk System Owner,

Validation Team QA
Assessment Process Owner, SME

Verification

Installation Vendor/ Validation System Owner,

QA
Qualification Team Process Owner, SME

Operational Vendor/Validation System Owner,

QA
Qualification Team Process Owner, SME

Performance Vendor/Validation System Owner,

QA
Qualification Team Process Owner, SME

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 Validation
Prepared Reviewer(s) Approver(s)
Deliverable

Requirements System Owner,

Validation Team QA
Traceability Matrix Process Owner, SME

Reporting

Validation Summary System Owner,

Validation Team QA
Report Process Owner, SME

European Union
EMA: European Medicines Agency
History: EU GMP Annex 11 for computerized systems has been an active part of EU GMP
since 1992. In 2008, the European Medicines Agency issued a proposed update that also
consisted of a principle and 19 clauses, this was a major change to the regulation that
incorporated regulatory concerns noted by inspectors with all types of computerized systems.
The Annex 11 was added to 2nd version of EudraLex GMP Guidelines. In 2006 EMEA
recommended a committee to update the Annex 11-Computerised Systems and Chapter 4-
Documentation.
The Final Version of Annex 11 was issued in January 2011 and effective on 30 th June 2011.

Brexit: “British Exit”

The withdrawal of the United Kingdom (UK) from the European Union (EU) and the
European Atomic Energy Community in January 2020.

The United Kingdom (UK) formally left the European Union (EU) on 31 January 2020 and
became a third country. During a transition period from 1 February to 31 December 2020, EU
pharmaceutical law continued to apply to the UK. From 1 January 2021, EU pharmaceutical
law applies to the UK in respect of Northern Ireland only.

Directives: Legal Acts that require EU member states to achieve a specified result
EudraLex: European Union drug Legislation Medicinal Products for Human Use

Collection of Rules and Regulations governing medicinal products within the European union.

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Drug Approval Process:
There are 2 regulatory Steps to go through before a drug is approved to be marketed in the
European Union.
1. Clinical Trial Application

2. Marketing Authorization application

Clinical Trial applications are approved at the member state level.
One should apply for Marketing Authorization application (MAA) before a drug is approved
to be marketed in the European Union after successful clinical trials.
Marketing Authorization applications should get approved at both the member state and
Centralized levels.

Depending on the type of drug product and time intended market, there are four different
types of Marketing Authorization applications. They are:

1. Centralized Procedure
2. Mutual Recognition Procedure
3. National authorization procedure

4. Decentralized Procedure.

Centralized Procedure
The European Union-wide procedure for the authorization of medicines, where there is a single
application, a single evaluation and a single authorization throughout the European Union.
Only certain medicines are eligible for the centralized procedure.
If a product has been authorized using the centralized procedure it has been assessed on an EU
wide basis and approved by the European Commission.

Mutual Recognition Procedure:

Once a drug is approved for marketing authorization by one-member state, it is eligible to apply
for marketing authorization in other member states through the mutual recognition procedure.
Identical applications are submitted to those member states where marketing authorizations are
sought.

The first member state that reviews the application is called the “Reference member state”
(RMS), it notifies the other states, called “Concerned Member States” (CMS).

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Incase if the concerned member states reject the mutual recognition, the matter is referred to
the CHMP of the EMA for Arbitration and then EMA forwards its opinion to the European
Commission which makes the final decision.

National Procedure:
National Procedure is used whenever a company wants to commercialize a product in only one
EU member state. It is specific to each country. Each country within the EU has its own
procedures for authorizing a marketing application for a new drug.

Respective information regarding requirements and procedure of each country can get from the
particular websites of the regulatory agencies.

Decentralized Procedure:
The objective of this procedure is to obtain marketing authorization in several member states,
when no marketing authorization has been granted in the European Community.
The applicant should send an application to the competent authorities of each of the member
states, where there is intent to obtain a marketing authorization.

Scientific Committees of EMA:

CHMP Committee for Medicinal Products for Human Use
PRAC Pharmacovigilance Risk Assessment Committee
CAT Committee for Advanced Therapies
CVMP Committee for Medicinal Products for Veterinary Use
HMPC Committee on Herbal Medicinal Products
COMP Committee for Orphan Medicinal Products
PDCO Pediatric Committee
IMPD Investigational Medicinal Product Dossier

EudraLex Consists of 10 Volumes, they are:

EU Pharmaceutical legislation for medicinal products for human
Volume 1.
use
Notice to applicants and regulatory guidelines for medicinal
Volume 2.
products for human use

Volume 3. Scientific guidelines for medicinal products for human use

Guidelines for Good Manufacturing Practices for medicinal
Volume 4.
products for human and veterinary use

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 EU Pharmaceutical legislation for medicinal products for
Volume 5.
veterinary use
Notice to applicants and regulatory guidelines for medicinal
Volume 6.
products for veterinary use

Volume 7. Scientific guidelines for medicinal products for veterinary use

Volume 8. Maximum residue limits

Guidelines for Pharmacovigilance for medicinal products for
Volume 9.
human and veterinary use

Volume 10. Guidelines for Clinical Trials

Volume 4: Guidelines for good manufacturing practices for medicinal products for
human and veterinary use
Volume 4 is Divided into 3 parts:
Part 1: Basic Requirements for Medicinal Products
Part 2: Basic Requirements for active Substances used as starting materials
Part 3: GMP-Related Documents

Part 1: Basic Requirements for Medicinal Products

Chapter 1. Pharmaceutical Quality Systems
Chapter 2. Personnel
Chapter 3. Premise and Equipment
Chapter 4. Documentation
Chapter 5. Production
Chapter 6. Quality Control
Chapter 7. Outsourced Activities
Chapter 8. Complaints and Product Recalls
Chapter 9. Self-Inspection

Annex 1 Manufacture of Sterile Medicinal Products

Annex 2 Manufacture of Biological Active Substances and Medicinal Products
Annex 3 Manufacture of Radiopharmaceuticals

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 Annex 4 Manufacture of Veterinary Medicinal Products other than
Immunological Veterinary Medicinal Products
Annex 5 Manufacture of Immunological Veterinary Medicinal Products
Annex 6 Manufacture of Medicinal Gases
Annex 7 Manufacture of Herbal Products
Annex 8 Sampling of Starting and Packing Materials
Annex 9 Manufacture of Liquids, Creams and Ointments
Annex 10 Manufacture of Pressurized Metered Dose Aerosol Preparations for
Inhalation
Annex 11 Computerized Systems
Annex 12 Use of Ionizing Radiation in the Manufacture of Medicinal Products
Annex 13 Manufacture of Investigational Medicinal Products
Annex 14 Manufacture of Products derived from Human Blood or Human
Plasma
Annex 15 Qualification/Validation
Annex 16 Certification by a Qualified Person and Batch Release
Annex 17 Parametric release
Annex 19 Reference and Retention Samples

EU GMP: Volume 4, Annex 11 – Computerized Systems

1 Risk Management
2 Personnel
3 Suppliers and Service Providers
4 Validation
5 Data
6 Accuracy Checks
7 Data Storage
8 Printouts
9 Audit Trails
10 Change and Configuration Management
11 Periodic Evaluation
12 Security

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 13 Incident Management
14 Electronic Signatures
15 Batch Release
16 Business Continuity
17 Archiving

Annex 11 – Computerized Systems, Section 4: Validation

 The Validation documentation and reports should cover the relevant steps of the life
cycle.
 Should be able to justify standards, protocols, acceptance criteria, procedures and
records based on the risk assessment.
 User Requirements Specifications should describe the required functions of the
computerized system and be based on documented risk assessment and GMP impact.
 User requirements should be traceable throughout the life-cycle.
 For critical systems an up-to-date system description detailing the physical and logical
arrangements, data flow and interfaces with other systems or processes, any hardware
and software pre-requisites and security measures should be available.
 The regulated user should take all reasonable steps to ensure that the system has been
developed in accordance with an appropriate Quality Management System.
 The Supplier should be assessed appropriately.
 Documentation supplied with Commercial-off-the-shelf products should be reviewed
by regulated users to check that user requirements are fulfilled.
 Evidence of appropriate test methods and test scenarios should be demonstrated.
Particularly, system parameter limits, data limits and error handling should be
considered.
 Validation documentation should include Change Control records and reports on any
deviations observed during the validation process.
 If data are transferred to another data format or system, validation should include
checks that data are not altered in value and/or meaning during this migration process.
 Computerized systems exchange data electronically with other systems should include
appropriate built-in checks for the correct and secure entry and processing of data, in
order to minimize the risks.

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Difference between and EU Annex-11 and US FDA, 21 CFR Part 11:
S. No Part 11 Annex 11
1 Detailed information about legacy No Information about Legacy Systems
systems
2 Discussed in detail about E- Electronic Signature
Signature and Digital Signature
3 For GMP Systems Critical Systems

4 No details about agreement Details about formal agreement

5 Record Copying is explained Printing information is explained

6 No much details about vendor Detailed information about vendor evaluation

evaluation
7 Personnel should have Education, Personnel-Appropriate Qualifications, level
Experience and Training of access and defined responsibilities and
close cooperation
8 Detailed information about Open Short information about open system
and Closed system
9 Applicable to regulatory submission No information about regulatory submission
documents documents

ISO: International Organization for Standardization

ISO is an independent, non-governmental international organization with a membership of 165
national standards bodies.
Through its members, it brings together experts to share knowledge and develop voluntary,
consensus-based, market relevant International Standards that support innovation and provide
solutions to global challenges.

It is dedicated to developing voluntary standards that ensure product safety and quality while
encouraging innovation in a global marketplace.
ISO Standards are a key part of our society as they ensure quality and safety in both products
and services in international trade. Businesses can be seen to benefit from ISO standards as
they can help cut costs by improved systems and procedures put in place.

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 ISO 9000 Quality Management System

ISO/IEC 27001 Information Security Management

ISO 45001 Occupational Health and Safety

ISO 14000 Environmental Management System

ISO 13485 Medical Devices

ISO 22000 Food Safety Management

ISO/IEC 17025 Testing and Calibration Laboratories

ISO 31000 Risk Management

ISO 50001 Energy Management

ISO 26000 Social Responsibility

Medical Devices
An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other
similar or related article, including a component part or accessory which is:

 recognized in the official National Formulary, or the United States Pharmacopoeia, or

any supplement to them,
 intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease in man or other animals, or
 intended to affect the structure or any function of the body of man or other animals
 And does not achieve its primary intended purposes through chemical action within or
on the body of man or other animals and which is not dependent upon being
metabolized for the achievement of its primary intended purposes.
 The term "device" does not include software functions excluded pursuant to section
520(o).

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Medical devices are classified into Class I, II, and III.
Regulatory control increases from Class I to Class III. The device classification regulation
defines the regulatory requirements for a general device type.
Most Class I devices are exempt from Premarket Notification 510(k);
Most Class II devices require Premarket Notification 510(k);

Most Class III devices require Premarket Approval.

 FDA's Center for Devices and Radiological Health (CDRH) is responsible for
regulating firms who manufacture, repackage, relabel, and/or import medical devices
sold in the United States.
 The Food and Drug Administration (FDA) is revising the current good manufacturing
practice (CGMP) requirements for medical devices and incorporating them into a
quality system regulation.
 This action is necessary to add preproduction design controls and to achieve
consistency with quality system requirements worldwide. This regulation sets forth the
framework for device manufacturers to follow and gives them greater flexibility in
achieving quality requirements.
 The quality system regulation includes requirements related to the methods used in, and
the facilities and controls used for, designing, manufacturing, packaging, labelling,
storing, installing, and servicing of medical devices intended for human use.
 The primary FDA regulations applicable to medical device product software are 21
CFR 820.70(i), 21 CFR 820.30
 According to 21 CFR 820.70(i) the automated system must be qualified for its intended
use to ensure system Performance
 There must be an approved procedure and qualification protocol(s) in order to ensure
that qualification is properly performed.

According to the FDA, software development is primarily a design process. 21 CFR 820.30
contains the design control regulations applicable to medical devices. The application of this
section to product software includes all design activities necessary to obtain, review,
implement, and validate a design specification.
In the context of Part 11, one of the differences between Parts 211 and Part 820 is the scope of
the electronic records that must be maintained.
Part 211 requires the maintenance of electronic regulated data including raw data. Part 820
requires that the results of acceptance activities are recorded, but not necessarily all of the raw

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regulated data. The exception in 820 is that raw data is required during failure investigations.
As in Part 211, results under Part 820 must have audit trails.

21 CFR Part 801 - Labelling

21 CFR Part 803 - Medical Device Reporting

21 CFR Part 807 - Establishment Registration

21CFR Part 807 - Medical Device Listing

21 CFR Part 807 - Premarket Notification 510(k)

21 CFR Part 814 - Premarket Approval (PMA)

21CFR Part 812 - Investigational Device Exemption (IDE)

21 CFR Part 820 - Quality System Regulation (QS regulation)

21 CFR Part 820: Pharmaceutical Quality System Regulations:

Subpart A - General Provisions
 Sec. 820.1 – Scope
 Sec. 820.3 – Definitions
 Sec. 820.5 – Quality System
Subpart B - Quality System Requirements
 Sec. 820.20 – Management Responsibility
 Sec. 820.22 – Quality Audit
 Sec. 820.25 – Personnel
Subpart C - Design Controls
 Sec. 820.30 – Design Controls
Subpart D - Document Controls
 Sec. 820.40 – Document Controls
Subpart E - Purchasing Controls
 Sec. 820.50 – Purchasing Controls
Subpart F - Identification and Traceability

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  Sec. 820.60 – Identification
 Sec. 820.65 Traceability
Subpart G - Production and Process Controls
 Sec. 820.70 – Production and Process Controls
 Sec. 820.72 – Inspection, Measuring, and test equipment
 Sec. 820.75 – Process Validation
Subpart H - Acceptance Activities
 Sec. 820.80 – Receiving, in-process, and finished device acceptance
 Sec. 820.82 – Acceptance Status
Subpart I - Nonconforming Product
 Sec. 820.90 – Nonconforming Product
Subpart J - Corrective and Preventive Action
 Sec. 820.100 – Corrective and Preventive action
Subpart K - Labelling and Packaging Control
 Sec. 820.120 – Device Labeling
 Sec. 820.130 – Device Packing
Subpart L - Handling, Storage, Distribution, and Installation
 Sec. 820.140 – Handling
 Sec. 820.150 – Storage
 Sec. 820.160 – Distribution
 Sec. 820.170 – Installation
Subpart M – Records
 Sec. 820.180 – General requirements
 Sec. 820.181 – Device Master Record
 Sec. 820.184 – Device History Record
 Sec. 820.186 – Quality System Record
 Sec. 820.198 – Complaint Files
Subpart N – Servicing
 Sec. 820.200 – Servicing
Subpart O - Statistical Techniques
 Sec. 820.250 – Statistical Techniques

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Definitions:
Medical Devices
Complaint means any written, electronic, or oral communication that alleges deficiencies
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a
device after it is released for distribution.

Component means any raw material, substance, piece, part, software, firmware, labeling, or
assembly which is intended to be included as part of the finished, packaged, and labeled device.

Control number means any distinctive symbols, such as a distinctive combination of letters
or numbers, or both, from which the history of the manufacturing, packaging, labeling, and
distribution of a unit, lot, or batch of finished devices can be determined.

Design history file (DHF) means a compilation of records which describes the design history
of a finished device.

Design input means the physical and performance requirements of a device that are used as a
basis for device design.

Design output means the results of a design effort at each design phase and at the end of the
total design effort. The finished design output is the basis for the device master record. The
total finished design output consists of the device, its packaging and labeling, and the device
master record.

Design review means a documented, comprehensive, systematic examination of a design to

evaluate the adequacy of the design requirements, to evaluate the capability of the design to
meet these requirements, and to identify problems.
Device history record (DHR) means a compilation of records containing the production
history of a finished device.

Device master record (DMR) means a compilation of records containing the procedures and
specifications for a finished device.

Establish means define, document (in writing or electronically), and implement.

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Finished device means any device or accessory to any device that is suitable for use or capable
of functioning, whether or not it is packaged, labeled, or sterilized.

Lot or batch means one or more components or finished devices that consist of a single type,
model, class, size, composition, or software version that are manufactured under essentially the
same conditions and that are intended to have uniform characteristics and quality within
specified limits.

Management with executive responsibility means those senior employees of a manufacturer

who have the authority to establish or make changes to the manufacturer's quality policy and
quality system.

Manufacturer means any person who designs, manufactures, fabricates, assembles, or

processes a finished device. Manufacturer includes but is not limited to those who perform the
functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or
specification development, and initial distributors of foreign entities performing these
functions.

Manufacturing material means any material or substance used in or used to facilitate the
manufacturing process, a concomitant constituent, or a byproduct constituent produced during
the manufacturing process, which is present in or on the finished device as a residue or impurity
not by design or intent of the manufacturer.

Nonconformity means the nonfulfillment of a specified requirement.

Product means components, manufacturing materials, in- process devices, finished devices,
and returned devices.

Quality means the totality of features and characteristics that bear on the ability of a device to
satisfy fitness-for-use, including safety and performance.

Quality audit means a systematic, independent examination of a manufacturer's quality system

that is performed at defined intervals and at sufficient frequency to determine whether both
quality system activities and the results of such activities comply with quality system
procedures, that these procedures are implemented effectively, and that these procedures are
suitable to achieve quality system objectives.

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Quality policy means the overall intentions and direction of an organization with respect to
quality, as established by management with executive responsibility.

Quality system means the organizational structure, responsibilities, procedures, processes, and
resources for implementing quality management.

Remanufacturer means any person who processes, conditions, renovates, repackages,

restores, or does any other act to a finished device that significantly changes the finished
device's performance or safety specifications, or intended use.

Rework means action taken on a nonconforming product so that it will fulfill the specified
DMR requirements before it is released for distribution.

Specification means any requirement with which a product, process, service, or other activity
must conform.

Validation means confirmation by examination and provision of objective evidence that the
particular requirements for a specific intended use can be consistently fulfilled.

Process validation means establishing by objective evidence that a process consistently

produces a result or product meeting its predetermined specifications.

Design validation means establishing by objective evidence that device specifications conform
with user needs and intended use(s).

Verification means confirmation by examination and provision of objective evidence that

specified requirements have been fulfilled.

A device identifier - a mandatory, fixed portion of a UDI that identifies the specific version or
model of a device and the labeler of that device; and

A production identifier - a conditional, variable portion of a UDI that identifies one or more
of the following when included on the label of the device.

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Quality Policy: Management with executive responsibility shall establish its policy and
objectives for, and commitment to, quality. Management with executive responsibility shall
ensure that the quality policy is understood, implemented, and maintained at all levels of the
organization.

Design validation: Each manufacturer shall establish and maintain procedures for validating
the device design. Design validation shall be performed under defined operating conditions on
initial production units, lots, or batches, or their equivalents. Design validation shall ensure that
devices conform to defined user needs and intended uses and shall include testing of production
units under actual or simulated use conditions. Design validation shall include software
validation and risk analysis, where appropriate. The results of the design validation, including
identification of the design, method(s), the date, and the individual(s) performing the
validation, shall be documented in the DHF.

Document changes: Changes to documents shall be reviewed and approved by an

individual(s) in the same function or organization that performed the original review and
approval, unless specifically designated otherwise. Approved changes shall be communicated
to the appropriate personnel in a timely manner. Each manufacturer shall maintain records of
changes to documents. Change records shall include a description of the change, identification
of the affected documents, the signature of the approving individual(s), the approval date, and
when the change becomes effective.

Automated processes. When computers or automated data processing systems are used as part
of production or the quality system, the manufacturer shall validate computer software for its
intended use according to an established protocol. All software changes shall be validated
before approval and issuance. These validation activities and results shall be documented.

Calibration: Calibration procedures shall include specific directions and limits for accuracy
and precision. When accuracy and precision limits are not met, there shall be provisions for
remedial action to reestablish the limits and to evaluate whether there was any adverse effect
on the device's quality. These activities shall be documented.

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 Quality Control: Technical Glossary
S. No Term Definition
1. Acceptance Criteria Numerical limits, ranges, or other suitable measures for
acceptance of test results .
2. Acceptance Limit The maximum amount of carryover of one product or cleaning
agent allowed in a batch or dose.
3. Acceptance Sampling Inspection used to determine whether a batch conforms or not to
visual inspection acceptance criteria.
4. Accuracy The closeness of agreement between the value which is accepted
either as a conventional true value or an accepted reference value
and the value found.
5. Action Limit/Action A level that, when exceeded, indicates a drift from normal
Level operating conditions. Action limits are based on design criteria,
regulatory/industry standards, and intended use of the area.
6. Adverse Trend (AT) A continuing deviation from normal “expected” process, product
or quality performance characteristic, that has potential severity
impact on safety, purity, efficacy or quality of the intended
product function.
7. AQL (Acceptance Quality level that is the worst tolerable process average when a
Quality Limit) continuing series of lots is submitted for acceptance sampling.
8. AQL Inspection Statistical inspection by attributes based on AQL
9. Attribute Data Data that consist of counts (i.e. number of defectives in a lot, pass
or fail, yes or no) of defects or defectives in a lot. Typically
counts of defective lots or of defects within lots are used.
10. Calibration The set of operations which establish, under specified conditions,
the relationship between values indicated by a measuring
instrument or measuring system, or values represented by a
material measure, and the corresponding known values of a
reference standard.
11. Centre Line (CL) Mean value of the control chart statistic
12. Control Charts Control charts are a graphical method for comparing information
from samples representing the current state of a process against

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 limits established after consideration of inherent process
variability. Their primary use is to provide a means of evaluating
if a process is or is not in a “state of statistical control”.
13. Control Limits Control limits are used as criteria for signalling the need for
assessment or for judging whether a set of data does or does not
indicate a “state of statistical control”. · Lower Control Limit
(LCL) – Minimum value of the control chart statistic that
indicates statistical control · Centre Line (CL) – Mean value of
the control chart statistic · Upper Control Limit (UCL) –
Maximum value of the control chart statistic that indicates
statistical control
14. Critical Process A process parameter whose variability has an impact on a critical
Parameter (CPP) quality attribute and therefore should be monitored or controlled
to ensure the process produces the desired quality.
15. Critical Quality A physical, chemical, biological or microbiological property or
Attribute (CQA) characteristic that should be within an appropriate limit, range,
or distribution to ensure the desired product quality.
16. Defect A departure of a quality characteristic that results in a product,
process or service not satisfying its intended usage requirements.
17. Failure Mode The manner by which a failure is observed; it generally describes
the way the failure occurs.
18. Histogram A histogram is a graphic display (bar chart) of the frequency
distribution (showing shape, location and variation on a number
line) of a data set. The x-axis is divided into equal size “bins” or
segments of the numerical data. The y-axis is the count of
occurrences of data in each segment of the data. The height of
the bar for each segment is proportional to the frequency of
occurrence of sample data falling into that category. Categories
must not overlap and must be equal in size.
19. Individual (I) Chart The individual chart plots each measurement as a separate data
point
20. Individual Moving The I-MR chart is made up of an individual chart and moving
Range (I-MR) Chart range chart.

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21. In-Process Controls Checks performed during production in order to monitor and, if
appropriate, to adjust the process and/or to ensure that the
intermediate or API conforms to its specifications.
22. Inspection by Attributes Inspection where the unit is classified as conforming or
nonconforming with respect to a specified requirement or set of
specified requirements.
23. Inspection Level (AQL Relationship between lot or batch size and the sample size.
based inspections only)
24. Intermediate precision Variation in the measurements made by different operators
and/or instruments and/or times in one laboratory from the same
sample.
25. Key Performance A measured or calculated attribute (typically characterizing the
Indicator (KPI) output of a process step) that is indicative of whether a process
step has met its goal. KPIs are routinely measured and should be
trended.
26. Lifecycle All phases in the life of a product from the initial development
through marketing until the product’s discontinuation
27. Lower Control Limit Minimum value of the control chart statistic that indicates
(LCL) statistical control.
28. Moving Range (MR) The MR chart plots the difference between two consecutive data
Chart points as they come from the process in a sequential order.
29. Out of Control Limit Single result that is markedly different from others in a series as
confirmed by statistical evaluation, i.e., one point beyond
established control limits
30. Out of Expectation OOE results for the purposes of this document are anomalous,
(OOE) Result unexpected or unusual findings, that have not been classified as
either OOS or OOT, for both qualitative or quantitative testing.
31. Out of Specification All reportable results not meeting established specifications. A
(OOS) confirmed reportable value that is outside the acceptable
specification criteria as stated in the product or analyte
specification (e.g. CoAs, USP).
32. Out of Trend (OOT) A test result or pattern of results that are outside of pre-defined
limits.

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33. Outlier A single result which is markedly different from others in a series
as confirmed by statistical evaluation.
34. Prediction Interval (PI) An interval that contains a future observation with a
predetermined confidence usually 95% or 99%.
35. Process Capability Index A statistical measure of process capability. Process Capability
Indices are measured in terms of proportion of the process output
that is within product specification or tolerance
36. Process Capability Process capability can be defined as the natural or inherent
behaviour of a stable process that is in a state of statistical
control. It is a statistical estimate of the outcome of a
characteristic from a process that has been demonstrated to be in
a state of statistical control
37. Process Parameters The variables or conditions of the manufacturing process or in an
in-process test on which a processing decision is based.
38. Random Sample A random sample is defined as one in which the entire population
has an equal chance of being selected to ensure representative
sampling across the batch.
39. Range Interval comprising an upper and lower range of an attribute or
variable
40. Real-Time Trend Trend analysis that is performed on applicable tests prior to lot
Analysis release and as soon as practically possible after each test result is
produced and analyzed.
41. Repeatability Variation in measurements obtained with one measuring
instrument when used several times by an operator while
measuring the identical characteristic on the same part or parts
from the same sample.
42. Reproducibility Variation in the measurements made by different operators
and/or instruments and/or times and in different laboratories
from the same sample.
43. Robustness The measure of a method’s capacity to remain unaffected by
small, but deliberate variations in method parameters and
provides an indication of its reliability during normal usage.

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44. Sample A portion of supply chain material collected according to a
defined sampling procedure.
45. Sampling Inspection The inspection of products using one or more samples (e.g.
simple, double, multiple, sequential, skip-lot, etc.).
46. Sampling Plan Combination of sample size(s) and associated lot/batch
acceptability criteria
47. Sampling Size The number of items statistically selected from a defined
population. Sample size is always an integer value.
48. State of Control A condition in which the set of controls consistently provides
assurance of continued process performance and product quality.
49. State of Statistical A process is considered to be in a “state of statistical control” if
Control it is affected by random (common) causes only, i.e. if no
Tolerance Intervals (TI)
extraordinary, unexpected, special causes have entered the
system.
An interval within which a stated proportion of a population will
lie at a stated confidence level.
50. Trend Drift Six consecutive points all increasing or decreasing
51. Trend Limits Upper and lower limits for evaluating potential trends; calculated
with prediction intervals.
52. Trend Shift Nine consecutive points on the same side of the centre line
53. Trend An evaluation for significant changes in the data over time.
54. Trending Trending is the search for significant changes in the data over
time. Unplanned or unexplained trends indicate lack of
consistency and stability.
55. Upper Control Limit Maximum value of the control chart statistic that indicates
(UCL) statistical control.
56. Western Electric/Nelson Decision rules for detecting "out-of-control" or non-random
Rules conditions on control charts.

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