ISO series, guide of pharmaceutical manufacturing facilities, productivity by kailash vilegave

Seminar on ……

ISO series, guide of pharmaceutical
manufacturing facilities, productivity

By :
Mr. Kailash Vilegave.
Assit prof.
Shivajirao S Jondhle college of
pharmacy Asangaon 421601

Department of Pharmaceutics 9/2/2012 1

Contents

 Introduction.
 History.
 ISO: 9000 series.
 ISO:14000 series.
 Guide to Pharmaceutical Manufacturing
Facilities, Productivity.
 References.


Introduction
What are ISO 9000 Standards?

 ISO 9000 Standards
 Define the required elements of an effective quality
management system
 Can be applied to any company
 Adopted by the United States as the ANSI/ASQC Q90
series.

STANDARD BODIES
154 COUNTRIES
Bureau of Standards Jamaica


Background Who Created Standards

• ISO WAS FORMED FEBRUARY 23, 1947 IN
GENEVA
• FIRST FAMILY OF QUALITY STANDARD
RELEASED 1987
– To eliminate country to country differences
– To eliminate terminology confusion
– To increase quality awareness
• FIRST ENVIRONMENTAL STANDARD
RELEASED IN 1996


How did ISO get started?

1906 - International Electro-technical Commission
1926 - International Federation of the National Standardizing
Associations (ISA)

1946 London - delegates from 25 countries decided to create a new
international organization "the object of which would be to facilitate the
international coordination and unification of industrial standards

1947 - ISO began to officially function
1951 - The first ISO standard was published
"Standard reference temperature for industrial length
measurement".


ISO 9000 Consists of 5
Documents
ISO 9000 Quality Management and Quality Assurance Standards

ISO 9001 Quality Systems - QA Model for Design/Development,
Production, Installation, and Service

ISO 9002 Quality Systems - QA Model for Production and Installation (no
design)

ISO 9003 Quality Systems - QA Model for Final Inspection and Test

ISO 9004 Quality Management and Quality System Elements -
Guidelines


ISO 9000 Family of Standards
•ISO 9000-2 - Generic guidelines for applying ISO 9001, ISO 9002, and
•ISO 9003

ISO 9000-3 - Guidelines for applying ISO 9001 to the
development, supply, and maintenance of software

ISO 9000-4 Application for dependability management

ISO 9004-2 Guidelines for services
ISO 9004-3 Guidelines for processed material
ISO 9004-4 Guidelines for quality improvement
ISO 9004-5 Guidelines for quality plans

•ISO 9004-6,7- Guidelines for project & configuration management


What has ISO Accomplished?
• ISO film speed code
• TL9000 Standard format for telephone and banking cards
• ISO 9000 which provides a framework for quality
management and quality assurance
• ISO 14000 series provides a similar framework for
environmental management
• Internationally standardized freight containers
• Standardized paper sizes.
• Automobile control symbols
• ISO international codes for country names, currencies
and languages
• AS 9100 the Aerospace Basic Quality System Standard


ISO 9000:1987 series ISO 9000:1994 series

International Organisation ISO 9000 was revised in
for Standards (ISO) adopted 1994
a series of quality
standards, ISO 9000:1987 greater emphasis on quality
assurance via preventive
based on BS5750 actions.
strongly influenced by the required evidence of
US Department of Defence compliance with
Military Standards documented procedures
(MILspecs).
tended to create a
initial version was focused significant volume of
on quality control using associated procedure
retroactive checking ("do it as you document it")
and corrective actions. manuals and bureaucracy.

QS-9000 ISO9000:2000 series

Ford, Chrysler, General
2nd revision of Quality
Motors and other
Management System
automotive/truck Requirement Standard from
manufacturers identified International Organization for
deficiencies in Standards
ISO9000:1994
moved towards
undertook a reprocess performance metrics
interpretation and reduced the need for
extension to develop QS- documented procedures
9000 where clear evidence exists
that the process is working
additionally addressed
well.
continuous
improvement, manufacturin Replacement for previous ISO
g capability and production 9001 / 9002 and 9003
part approval processes. standards of 1994

ISO9000:2000 Future
series Version : 2008
 standards provide criteria for
companies to TC 176, the ISO 9001
 "certify" their quality
technical committee
management
, has started its review on
the next version of ISO
 recertification is required 9001, which will in all
every three years likelihood be termed the
 achieve "registration" by third- ISO 9001:2008
party auditor. standard, assuming its
planned release date of
 the system 2008 is met. Early reports
 verifies practice and are that the standard will
processes not be substantially
 provides objective 3rd
changed from its 2000
version.
party validation
 enables benchmarking.


New ISO 9001

Management
Responsibility

Measurement,
General Resource analysis & General
requirements management QMS
improvements requirements

Product
Realization

Continual Improvement cycle

ISO 9001: Model
Continual Improvement of
the Quality Management System

5.Management
Responsibility

CUSTOMERS
CUSTOMERS

Quality Management

Satisfaction
6. Resource 8. Measurement
Analysis and
Management Improvement

System

7. Product
Requirements Product Consumption
Realization

Principle Of New Standards

Customer
focus
Mutual
beneficial
supplier
relationshi Based on eight
p quality
management
Factual
principles
approach
to
decision
making System
Continual approach
improveme to
nt Manageme
nt

Principles of new standard
Customer focus
•Organization depends customers
•Understand current & future customer needs.
•Meet / exceed customer expectations

Leadership
•Leaders establish purpose & direction of the organization
•Should create & maintain environment to achieve
organization’s objectives

Involvement of People
•People of all levels are essence of an organization
•Their full involvement for organization’s benefit

Process approach
Desired results are achieved more efficiently when activities and
resources are managed as process


Principles of new standard
System approach to Management
Identifying, understanding and managing interrelated process as a
system contributes to the organization’s effectiveness & efficiency

Continual improvements
Continual improvement of the organization’s overall performance
should be a permanent objective of the organization

Factual approach to decision making
Effective decisions are based on the analysis of data and information

Mutually beneficial supplier relationships
•An organization & its suppliers are interdependent
•Mutually beneficial relationship enhances the ability of both to
create value

Expectations of the new
Standard
Avoid the application of systems that are separate from the
organization’s business process

Enable the development of a Quality system that is fully
integrated into the normal operations of organization’s business

Enable Continual improvements of the system for enhanced
customer satisfaction

Enable compliance to statutory & regulatory requirements


Important changes

Criteria Previous version New Version
Main focus Products Customer satisfaction

Approach 20 quality elements Value adding processes

Product requirements Requirements specified by + Statutory & regulatory
customer / organization requirements

Involvement of What to do, When, Whom & How + Why it is to be done
people to do

Improvements Maintain the system Continual improvements
requirements should be achieved


Process approach
Process definition
Set of interrelated or interacting activities which transforms
inputs into outputs

Identify the Ensure
Identify Identify Establish
Interaction continual
the the Inputs measurin
s to other improvemen
processes & outputs g criteria
processes ts

Do it for all value adding processes


Process approach –
Continual improvements of Process

Understandings &
meeting requirements
PLAN

Continual improvements
Processes in terms
of Processes based on
Of Added Value PDCA Cycle
objective measurements
DO
ACTION

Measure results of process
Performance and effectiveness
- Objective Measurements
CHECK

System Requirements / Structure of the
Standard
4 Quality 5 ISO9000 6 ISO9000 7 ISO9000 8 ISO9000
Manageme structure I structure II structure structure
nt System Management Resource III Product IV
Responsibility Management Realization Measureme
nt Analysis
General Management Provision of &improveme
Planning
requirements Commitment resources nt

Customer General
Documentation Customer focus Human
Requirements resources related
processes
Monitoring &
Quality policy Infrastructures measurement
Design &
development
Control of NCP
Planning Work
environment Purchasing
Analysis of data
Responsibility,
authority & Production &
communication service Improvements
provision

Management
Reviews

4 - Quality management system

Identification
Continual of processes
improvements required

4.1 General
Criteria and
requirements
Monitoring and methods to ensure
Measuring of Operation & control
processes
Availability of
information &
resources for
operation & control


4 - Quality management system

4.2 Document requirements

Quality Policy

Quality Objectives

Quality Manual

Procedures required by the Standard

Procedures required for planning, operation
& control of Organization activities

Records

5 - Management Responsibility

5.1 5.2 5.3 5.4 5.6 5.7
Management Customer Quality Planning Responsibility Management
commitment focus policy authority & Review
communicate

Quality Responsibility General
objectives & authority
Review
QMS Management inputs
planning representative
Review
Internal outputs
communication


5 - Management Responsibility

Development, implementation and
continually improvement of QMS

Establishment of
•Quality Policy
•Quality Objectives
Top
Management’s
Identification of Customer requirements
commitment

Communication of importance of
•Appointment of Management •Regulatory & statutory requirements
Representative •Meeting customer requirements
•Conducting Management •Quality Policy & Quality objectives
Reviews •Responsibilities & authorities

•Providing required resources


6 - Resource Management

6.1 6.2 6.3 6.4
Infrastructures
Provision of Human Work
resources Resources Environment

General

Competence,
awareness &
training


6 - Resource Management

Resources required to
Implementing, monitoring & continual
improvements
Enhance Customer satisfaction by
meeting customer requirements

Human Resources
Resource
Managemen
t Infrastructures
Infrastructures needed to achieve product
conformity

Work environment
Work environment needed to achieve product
conformity


6 - Human Resources

Competent on the basis of appropriate
education, skill and experience

Define competencies for people
performing work affecting product quality
6.2
Human
Provide training or actions
Resource
s
Evaluate effectiveness of the training /
actions

Employees should aware importance of the
activity being performed


7 - Product Realization

7.1 7.2 7.3 7.4 7.5 7.6
Planning Customer Design and Purchasing Production Control of
of product related development & service monitoring
processes provision measuring
realization devices

Identification of Design planning Purchasing Control
customer process
requirement
Design inputs Validation of
Purchasing processes
Review of Design outputs information
customer Identification &
requirement traceability
Design review Verification of
purchased
products
Customer Design Customer
communication verification property

Design validation Preservation of
product

Design Changes



Quality objectives of Products

Processes, procedures to realize
product
7.1
Planning of
Product
Verification, validation, monitoring, ins
realization pection and testing of product

Record to demonstrate conformance



Identification of Customer / Market
requirements
•Specified by customer
•Requirements taken for granted
7.2 •Statutory / Regulatory requirements
Customer related
processes – Review of requirements related
(Sales) product prior to acceptance /
commitment to customers - ability
to meet customer requirements

Effective communication with customer in relation to
•Product information
•Sales order handling
•Customer feedback
•Customer complaints


Planning
•Effective & efficient
•Expectations of interested parties

7.3
Design and
Development –
(Product) Design inputs and outputs

Review and verification, validation and control of changes
•Accuracy
•Potential hazards & faults
•Corrections
•Evaluations against lessons learnedPharmaceutics 9/2/2012
Department of 32


Degree of control depends on effects of
subsequent processes and effect on final
product

7.4
Purchasing
Supplier evaluation
Purchasing is done
in controlled
manner to ensure
that purchased
products conforms
to specific Verification of purchased product –
requirements Inspection and testing



Product
characteristics Procedures and work instructions

Suitable equipments to manufacture.
7.5
Monitoring and inspection & testing
Production and
service provision Product release, delivery and post
Manufacturing / delivery
service provision
under controlled Process validation
condition to ensure
conformity of product
Identification and
traceability

Customers property
Material supplied by customers – e.g.. 3rd party blending

8 - Measurement, analysis
and improvement
8.1 8.2 8.3 8.4 8.5
Control of
General Monitoring & non Analysis Improvement
measurements conforming of data
product

Customer Continual
satisfaction improvements

Internal audits Corrective
action
Measurement
of processes Preventive
action
Measurement
of product


and improvement
8.1 - To demonstrate
• Conformity of the product
• Conformity to QMS requirements
• Continually improvements and the effectiveness of the system

8.2 - Monitoring and Measurements
•Customer satisfaction / perception
•Internal audits - conformity planned arrangements of QMS and
ISO9001
•Monitoring and measurements of processes – to determine /
demonstrate ability of processes to achieve required results
•Monitoring and measurements of product – Conformity to
product requirements

8.3 - Control of NCP
•To assure that NCP products are identified and controlled to
prevent unintended use / delivery

and improvement

8.4 - Analysis of data
Collection and analysis of data generated through QMS
activities to verify suitability, effectiveness and continual
improvement of the system

Analysis shall provide information related to

•Customer satisfaction / perception
•Conformity to specs, requirements
•Trends of processes and products
• Opportunities for preventive actions
•Suppliers


and improvement
8.5 - Improvements
Continual Improvements
•QMS needed to be continually improved

Corrective action
•Actions to prevent recurrence of NCP, NCR etc
•Includes reviews, determination of causes, need of action,
implementation of action, review of action and maintenance
of relevant records

Preventive action
•Actions against potential non conformities to avoid their
occurrence
•Includes identification of potential non conformities, cause,
need for action, implementation of action, review of action
and maintenance of records

Criteria for measurements
–Satisfaction surveys for customers and other interested
parties
•Feedback on products
•Customer & market requirements

–Financial measurements
•Prevention cost
System
•Non conforming / failure cost
performanc •Lifecycle cost
e
Self assessment
–Internal audits
•Effectiveness & efficiency of processes
•Opportunities for improvements
•Use of data / information
•Effective & efficient use of resources
•Adequacy, accuracy and performance of measurements
•Relationships with customers/ suppliers/ other interested
parties

Criteria for measurements

–Process capability / process validation
Processe –Reaction time
s –Cycle time / throughput (Capacity)
–Utilization of technology
–Waste reduction
–Cost reduction

Products

–Inspection and testing of incoming, in process and final
product
–Product verification
–Product validation


What is ISO 14000?
Primarily concerned with Environmental Management

Minimize harmful effects on the environment

Continual Improvement of environmental performance

The formation of ISO Technical Committee 207 (TC 207) in 1993 marks
the beginning of the development of the ISO 14000 series. The US
Technical Advisory Group (TAG) for ISO/TC 207 (US/TAG for ISO/TC
207) represents the United States in international negotiation on ISO
14000

ISO 14000 ISO 14001
EMS- General Guidelines on EMS- Specification with
Principles, Systems and Guidance for Use requires a
Supporting Techniques substantial commitment of time
and resources

ISO 14004 ISO 14010
EMS - General Guidelines EA- General Principles of
on Systems, Principles and Environmental Auditing
Supporting Techniques
ISO 14012
ISO 14011 EA- Qualification Criteria for
EA- Auditing of Environmental Auditors
Environmental Management
Systems
ISO 14014
Initial Reviews
ISO 14013
ISO 14015
Management of
Environmental Audit Environmental Site Assessments
Programs
ISO 14021
ISO 14020
EL- Self Declaration-
EL- Basic Principles of
Environmental Claims- Terms
Environmental Labeling
and Definitions

ISO 14022 EL- Symbols ISO 14024
ISO 14023 EL- Practitioner Programs-
EL- Testing and Verification Guiding principles, practices
Methodologies and certification procedures
of multiple criteria (type1)
ISO 14031
ISO 14040
Environmental Performance
LCA- General Principles and
Evaluation
Practices
ISO 14041
ISO 14042
LCA- Goal and
LCA- Impact Assessment
Definition/Scope and
ISO 14043
Inventory Assessment
LCA- Improvement
ISO 14060 Assessment
Guide for the Inclusion of ISO 14050
Environmental Aspects in
Terms and Definitions
Product Standards

Guides To Pharmaceutical Manufacturing
Facilities & Productivity

 Quality
 Facilities and Equipment
 Materials
 Production
 Packaging/Labeling
 Laboratory Controls


Need of guidelines in pharmaceuticals
facilities & productivity
 Detailed guidelines of a system so that the
findings reflect the state of control in that
system for every product (profile) class
 If one of the six systems is out of control, the
firm is considered out of control
 A system is considered out of control based on
GMP deficiencies which suggest lack of
assurance of quality


Quality System

Quality must be built into the
process

Quality is not tested into the product
Quality
System Assurance of Quality comes from
- Design of robust process based on
thorough knowledge of that process and the
sources of variability

Effective Quality System in place


Role of Management in QS
 Management is responsible for:

 Organizational structure
 All Processes
 All Procedures
 Facilities & Resources

 In short, everything to insure product quality, customer
satisfaction and continuous improvement


Quality System Responsibilities

 Assures overall compliance 6) Reprocess/ Rework
with cGMPs 7) Validation/ Revalidation
 Review and approval duties 8) Rejects
for:
9) Stability Failures/ Out of
1) Product Quality Reviews (at trend data
least annually)
10) Quarantine products
2) Complaint reviews
11) Documented GMP & Job
3) Discrepancy/ failure Related Training
investigations
4) Change Control
5) CAPA (Corrective And
Preventive Action)


Laboratory Control System (I)
Adequately staffed laboratories (supervisory
and bench personnel)

Written specifications for raw
materials, intermediates, APIs, label
Laboratory Control s & packaging
System: Written procedures for sampling,
testing, approval or rejection of
Adequate lab facilities materials and for the recording and
under the Quality Unit storage of data
which is independent
from Production
Method validation/ revalidation

Validation and Security for computerized handling of test results
and related data; system for assuring integrity of all lab data

Laboratory Control System (II)
Reference Standards (primary; secondary)

Laboratory controls followed and
documented

Laboratory Control
System Calibration: written
procedures, schedule, documentation

Equipment Qualification

Written procedure (SOP) covering out of specification “oos” results


Laboratory Control System (III)

Investigation of “oos” results conducted in a timely
manner as per SOP and documented (complete
records maintained).

Laboratory Conclusions from “oos” investigations
Control documented and corrective actions/ need
System for addition investigation identified and
implemented.

“oos” review included in Product
Quality Reviews

Description of samples
Identification of method used
Raw data for sample/ standard preparation, reagents

Laboratory Control System (IV)
Complete record of all data from testing
Record of all calculations

Statement of the test results; how
compare with established acceptance
criteria

Laboratory Control
System
Signature of the person who performed
each test; dates tests performed

Date/ signature of second qualified person who reviewed original test
records for accuracy, completeness and compliance with established
standards

Training
(documente
d; job-
related)

Implementation
and
documentation Production
of in-process System (I)
controls, tests,
and
examinations

Contemporaneous, accura
te and complete batch
production documentation


Production system (II)

Adequate written procedures & practice
for charge-in of materials

Identification of equipment with contents,
stage of manufacturing, status

Equipment cleaning records

Established time limits for completion of
production steps/ stages

Deviations investigated and documented
contemporaneously with investigation

Production system (III)

Process validation based on knowledge of process
(scientific basis for identifying critical steps/
critical process parameters/control points)

Justification and consistency of in-process
specifications and final product specifications

Data/ information documented and available
to Quality Unit for review (trending, investigations etc.)


Facilities & Equipment System
Location, design, construction appropriate to facilitate
cleaning, maintenance, operations

Layout and air handling designed and
constructed to prevent cross-
contamination

Facilities &
Equipment Flow of materials & personnel designed
System to prevent mix-ups or contamination

Defined areas or other control systems to prevent mix-ups or
contamination includes as:

Incoming materials
(id, quarantine) Sampling area (prevent
contamination)

Quarantine (intermediates, APIs)

Facilities &
Released materials
Equipment
System
Rejection

b) EQUIPMENTS

Appropriate design, size, location, non-reactive product
contact surfaces

Identification clearly
marked Calibration

Preventive Maintenance schedule
and procedures

Facilities & Cleaning procedures and validation
Equipment
System: b) Records of
use, cleaning, maintenance
EQUIPMENTS
Closed or contained equipment. -
Inspection prior to use

Separate facilities or containment where needed (penicillin's, highly
potent compounds etc.)

Utilities
Qualified and appropriately monitored;
drawings should be available

Designed and constructed to prevent
contamination or cross-contamination

Utilities Recirculated air to production
(same concern)

Permanently installed pipe work should be
appropriately identified

Drains of adequate size with air break


Water
Process water at minimum meeting WHO
guidelines for potable water

Justify quality of water used to
achieve stated API quality and
establish specifications

Water
Water treatment facilities validation

API to be used for incorporation into sterile dosage form – water used in
later stages should be monitored and controlled for total microbial counts,
objectionable organisms and endotoxins

Materials System
Written procedures for receipt, identification,
quarantine, storage, handling, sampling, testing and
approval or rejection of materials

System to evaluate suppliers (critical materials)
Purchased against agreed specification

Materials
Change control process for
System changing suppliers

Upon receipt check for correct labeling,
seals
Before co-mingling bulk material, id/test

Assurances obtained from non-dedicated
tankers

Materials System
Identification on large storage containers and
associated manifolds, filling and discharge lines

Code given to received batches; status identity

Materials
At minimum, a specific identity test
System on incoming batches.

Supplier evaluation should include three
fully tested batches; one fully tested
batch/year

Written sampling plan with justification
Prevent contamination of sampled containers

Materials System
Stored in manner to prevent degradation,
contamination, no adverse effect on quality

Drums, bags, boxes off the floor

Materials
System First in, first out

Rejected materials identified and
controlled under a quarantine system

Established re-test/ re-evaluation periods

Packaging & Labeling System

Written procedures for receipt, identification,
quarantine, sampling, examination and/or testing P&L

P&L should conform to specifications

Records maintained for each shipment
(showing receipt, examination & result)

Containers protective, clean, not alter product
quality; if re-used, cleaned & labeling defaced

Access to label storage area limited

Written procedures for reconciliation;
- investigation if discrepancy


All excess labels with batch #, destroyed

Obsolete labels destroyed

Printing devices controlled to insure accuracy
of label (against batch record)

Print labels checked against master
and a copy placed into the batch record

Documented procedures to assure correct
packaging materials/ labels used

Operations designed to prevent mix-ups



Labels: API name, batch #, storage conditions

Shipped API: Name/ address manufacturer; special
transport conditions; expiry/ retest date

Documented clearance before operations

Packaged/ labeled intermediates or APIs
examined as part of packaging (documented)

Seal employed to assure package integrity


Benefits
 Certification demonstrates the recognition of quality
throughout organization

 Decrease in wasted time, materials, and efforts.

 Inculcating values of excellence and best practices.

 Establish leadership role within organization.

 Increased recognition by international partners

 Ability to maintain standards of quality and
excellence.


References

 Lachman L. Lieberman A. Kanig JL. The
Theory Of Industrial Pharmacy, 2nd edi,
Varghese Publication House; Bombay-14
 Gilbert s. Banker, Christoher T. Rhodes,
Modern Pharmaceutics, 3rd edi, New York.
 Sharma PP. How To Practice GMPs, 2nd edi,
Vandana Publication; Agra.
 www.google.com
 www.wikipedia.com
 www.kwaliteg.co.za.iso:9000.com
 www.fda.com


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