INDUSTRIAL PHARMACY II BP 702T (Theory)

UNIT-4

SYLLABUS-
Quality Management Systems: Quality management and Certifications: Concept of
quality, Total quality management, Quality by Design (QbD), Six-sigma concept,
Out of Specifications (OOS), Change control, Introduction to ISO 9000 series of
quality systems standards, ISO 14000, NABL, GLP.

*QUALITY MANAGEMENT SYSTEM-

-Quality Management System (QMS) is an important aspect for the pharmaceutical industry for
maintaining the quality and safety for their products and services.

-QMS relies on the regulations and guidelines to maintain the effective quality in
pharmaceutical industries.

-A management technique used for communicating to employees what is required to produce

the desired quality of products and services and to influence employee actions to complete
tasks according to the quality specifications is termed Quality Management System (QMS).

-QMS is a set of policies and procedures required for planning and execution in the core
business area of an organization ( i.e., area that can impact the organization’s ability to meet
customer requirements). An example of a QMS is ISO 9001.

-Quality can be defined according to US FDA as; “A measure of a product’s or service’s

ability to satisfy the customer’s stated or implied needs.”

-Purpose of QMS-
.Improving Process.
.Engaging Staff
.Setting organization-wide direction

Scope of Pharmaceutical QMS-

-According to US FDA, pharmaceutical QMS is applied to the development and manufacture

of pharmaceutical drug substances and drug products, including biotechnology and biological
products, throughout the product lifecycle.
- For the purpose of this guidance, the following technical activities can be included:
1-Pharmaceutical Development:
• Drug substance development.
• Formulation development (including container/closure system).
• Manufacture of investigational products.
• Delivery system development (where relevant).
• Manufacturing process development and scale-up.
• Analytical method development.

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2-Technology Transfer:
• New product transfers during development through manufacturing.
• Transfers within or between manufacturing and testing sites for marketed products.

3-Commercial Manufacturing:
• Acquisition and control of materials.
• Provision of facilities, utilities and equipment.
• Production (including packaging and labeling).
• Quality control and assurance.

*Total Quality Management (TQM)-

-The pharmaceutical industry is key part of the health care system.

-The regulation of this industry is very important because one mistake in production can cause
more severe condition in relation to health care system.
-So, the maintenance of the quality of the drugs is so important in pharmaceutical industries
because the poor quality of drugs can cause health hazards and economical burden for both the
government and patients.
-Total quality management is improvised in the industries to maintain the quality and safety of
the drugs and prevention of the defects rather than the detection.
-As per International Organization of Standard (ISO), TQM is defined as: “A management
approach of an organization centered on quality, based on participation of all its members and
aiming at long term benefits to all members of the organization and society”.
-Total - made up of the whole
Quality - degree of excellence a product or service provides
Management - act, art, or manner of planning, controlling and Directing.
Therefore, TQM is the art of managing the whole to achieve excellence.

Principles of TQM-
1. Produce quality work the first time and every time.
2. Focus on the customer.
3. Have a strategic approach to improvement.
4. Improve continuously.
5. Encourage mutual respect and teamwork.

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The key elements of the TQM-
Focus on the customer.
Employee involvement
Continuous improvement

Benefits Of TQM:
• Improved quality.
• Employee participation.
• Team work.
• Working relationships.
• Customer satisfaction.
• Employee satisfaction.
• Productivity.
• Communication.
• Profitability.
• Market share.

Tools used in TQM-

Tool Purpose
Cause and effect diagram/Fishbone diagram Identify and analyze causes of a problem
Checklists Gathering of data
Flowcharts Document detailed steps of a process
Scatter diagrams Relation between two variables
Control charts Identify variations in process
Histograms Graphical display of frequency distribution
of data
Pareto analysis Degree of importance of each element

*Quality by Design (QbD)-

-Pharmaceutical industries always rely on the continuous improvement in safety, quality and
efficacy of the products.

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-The pharmaceutical products are intended for the patient care.
-So, the priority is enhanced therapeutic benefits and absence of impurities.
-Therefore, the product should be designed to meet patients’ needs and the intended product
performance.
-The product quality and performance are regulated by finished product testing, with
understanding of the process and critical process parameters.
- According to US FDA and ICH Q8 (R2) the QbD is a systematic approach to development
which includes the prior knowledge of product and process understanding based on the results
of studies using design of experiments, use of quality risk management and use of knowledge
management.
- The concept of QBD was mention in ICH Q8 guidelines, which states that, “To identify
quality cannot be tested in products, i.e. Quality should be built into product by design.

Objectives of QbD-
The main objectives of QbD are as follows:
1. Increasing manufacturing efficiency.
2. Increasing the efficiency in product development.
3. Enhancement of product quality and performances to meet patients’ needs.
4. Increase in process capability.
5. Avoidance of regulatory compliances.
6. Incorporation of risk management.
7. Reduction in production costs and waste.
8. Reduction in product variability, defects and rejections.

Advantages:
Benefits for Industry:
Better understanding of the process.
Less batch failure.
More efficient and effective control of change.

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Elements of QbD-
The following elements can be included in the study of QbD:
1. QTPP (Quality Target Product Profile): This profile is related to quality, safety and
efficacy.
2. CQAs (Critical Quality Attributes): The study of CQAs helps in the study and controlling
of the product characteristics that have impact on product quality.
3. Determination of CQAs of drug substances, excipients, etc. and the selection of the
excipients to attain the desired drug quality.
4. Suitable manufacturing process selection.
5. Risk assessment:
• CMAs (Critical Material Attributes)
• CPPs (Critical Process Parameters)
6. Defining a control strategy.

*Six Sigma Concept-

-Six sigma concepts are a principle for the process improvement.
-Six sigma represents the quality level which is implemented for reducing the operational costs
in pharmaceutical industry and serving the best customer satisfaction and services.
-Six sigma is symbolized as “6σ”.
-Six sigma is a statistical measurement of product variables.
-This concept helps to achieve stable and predictable process results with continuous quality
improvement.
Aim of Six Sigma Concept-
The main aims of the six sigma concept are as follows:
1. Process improvement
2. Improved methodology
3. Improved quality
4. Customer satisfaction
5. Reduction in process variation
6. Reduction in costs
7. Fewer defects to achieve the goal
8. Continuous quality improvement

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Six Sigma Process-
-The concept is designed in “DMAIC” process.
-DMAIC stands for Define, Measure, Analyze, Improve and Control.
1. Define: ‘Define’ is the first and more difficult step of six sigma approach.
-The basic aim of this step is defining the problems and objectives.
-‘Define’ explains project goal, aim, difficulties, target magnitude and time span to achieve the
improved process.
2. Measure: This is the process of collecting expected data.
-The data will help to understand the magnitude of improvement and will answer either the
expected improvement can be measured or not.
-The data is not necessarily quantitative.
3. Analyze: This process includes the analysis of the whole process and helps to understand the
factors of influence.
- This is nothing but the analysis of raw data to establish a correlation between input variables
and the possible output that implies critical quality attributes (CQAs).
4. Improve: The next step is improvement of the process that has been outlined in the define
step to achieve the expected outcome and result.
5. Control: The improvement done in the last step should be retained and additional
procedures may be included in the workflow.

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OUT OF SPECIFICATIONS (OOS)-
-When an analytical or test result of any batch or material is out of predetermined limits or
specifications, it is called as OOS.
-Out-of-Specification (OOS) means that the test results for your sample do not meet the
accepted established criteria.
-These criteria may be set by your organization, or by the testing laboratory.
-OOS may be raised in the case of stability testing, analysis of in-process, test of raw materials,
intermediates and finished goods (API).
-Investigation for OOS may be performed while getting any unacceptable and questionable
results.

Identification of OOS:
1-PHASE I-Laboratory Investigation-
-This investigation is conducted when OOS is found in analysis.
-In the first phase of the OOS investigation the laboratory will assess the initial data and
determine if it was accurate.
Did the analyst who tested the sample make any errors in the testing process?
Were there any malfunctions with the testing instruments?
-If the laboratory determines that a laboratory error may have occurred, your sample may be re-
tested.
-If your sample is re-tested, a different analyst will perform the new test in order to rule out
analyst error.
-New Analyst should verify the followed correct procedure. He should overlook the following
points:
1. Raw data of the result.
2. Calculations of the result.
3. Proper functioning of instruments.
4. Procedure performed by the analyst.
5. Quality parameters of solvents, reagents, standard solutions.
6. Knowledge of the analyst regarding investigation.
7. Method validation and evaluation of performance.
8. Preservation of the results obtained.

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-If no clear laboratory error is identified, re-testing will not be performed.
-The main purpose of obtaining OOS reports is to find out the source of the results which fall
outside the specifications.
-If no testing error is found from the lab, and test results appear to be accurate, we move on to
the second phase of the investigation.

2-Phase II – Full-Scale Investigation at Facility

-When an initial analysis does not confirm the errors caused by OOS result from lab
investigations, full scale investigations with proper design should be performed.
-The following are the important aspects of OOS results identification with respect to full scale
investigation.
1. Review of manufacturing, production and sampling.
2. Review of lab investigation result.
3. Supplementary laboratory testing procedure.
-The goal of Phase II of an OOS investigation is to identify the root cause of the OOS results
so that proper corrective and preventive action can be taken.
-Within this phase, a review of the production may occur. Was there an inadequate amount of
raw material used? Was there some sort of variation during the manufacturing process? Was
the product formulation lacking robustness?

Change Control-
-In pharmaceutical industry change control is an important part of quality assurance.
-The changes proposed and made in any procedure or process should be reviewed, established,
documented and approved by the concerned authorities.
-Change control is the system to implement this approved change to confirm the regulatory
requirements.
-Change control can be defined as; “A formal system by which qualified representatives of
appropriate disciplines review proposed or actual changes that might affect the validated status
of facilities, systems, equipment or processes.

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Function-
The main functions of change control are:
1. Identification of the changes made.
2. Review of the change.
3. Approval of the change.
4. Validating the changes which can alter the product quality, regulatory or GMP (Good
manufacturing process) requirements.
5. Analysis of the change and monitoring of the impact of change.

Area of Change-
1. Manufacturing: Following changes are concerned:
• Raw materials
• Equipments
• Process/parameters
• Testing/validation procedures
• Packaging materials
• Cleaning process
2. Quality control and quality assurance: Following changes are considered:
• Quality testing parameters
• Sampling size
• Validation process
• Specifications of raw materials, intermediates and final product
• Documentation
• Standard operating procedures (SOPs)
3. Research and development: It includes the change in;
• Manufacturing process (any addition of elimination of steps)
• Raw materials (any addition of omission of the product)
• Specifications of raw materials, intermediates and final product
• Quantitative aspects of raw materials and finished products
• Manufacturing conditions and storage conditions.
4. Engineering: It includes the following changes in:
• Equipment used

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• Validation of the equipment
• Parts of equipment
• Working and design layout
• Software/ Hardware or Change in any program

ISO 9000 & ISO 14000-

-International Organization for Standardization (ISO) is an international standard of QMS.
-The written international standard is implemented by ISO.
-It is an independent organization with more than 150 national standard bodies.
-ISO standard is concerned with the-
• Standard development based on global expert opinion.
• Capacity building activities by technical assistance.
• Research and training for the education about standards.

ISO 9000-
The ISO 9000 family of standards is designed to help organizations to ensure the customers’
needs, the statutory and regulatory requirements.
-It does not certify any organization. It certifies the QMS of any organization.
-The basic quality management principles (QMP) of ISO 9000 are:-

ISO 9000 Series-

1-ISO 9000: Quality assurance and quality management concepts, guidelines for selection and
use.
2-ISO 9001: Concepts for QA in design, production and development of the system, along
with service and installation.
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3-ISO 9002: Concepts for QA in production, service and installation.
4-ISO 9003: Model for QA in final inspection and finished good testing.
5-ISO 9004: Guidelines for quality assurance and quality management planning,
implementation, efficiency and improvement.

ISO 14000-
-ISO 14000 family provides practical tools to manage the environmental responsibilities of
companies and organizations.
-It was initially published in 1996 and revised in 2004.
-This standard is related to Environmental Management System (EMS).
-ISO 14000 is considered as generic management system and it is applicable for the following:
• Any organization (single-site to large MNCs, high risk to low risk companies).
• The manufacturing industries (equipment manufacturers and suppliers), process industries
and service industries.
• All industries of local government, public and private sectors.

-The basic features of ISO 14000 are:

• Minimum harmful effects on environment.
• Continuous improvement to achieve the desired performances.

Principle of ISO 14000-

The principle of ISO 14000 is explained by PDCA Model.
1. Plan: Designing of aim, objective and processes to achieve the desired result.
2. Do: Designed process should be performed step by step.
-The changes are noted and data is stored to analyze the results.
3. Check: The evaluation of the data and results recorded in the previous steps.
4. Act: The evaluation of the data and results helps to improve the process.
-In this step, the problems of the result are rectified for the continuous improvement, for this
purpose, Do and Check steps may be repeated several times for the better outcome.

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Advantages of ISO 14000-
By getting ISO certification any organization can maintain their conformation to the
environmental regulations.
-This certification can help an organization by the following ways:
• Better marketability.
• Better utilization of resources.
• Environmental responsibilities.
• Better quality of finished goods and products.
• Customers’ satisfaction.
• Enhancement of the reputation and reliability of the organization.
• Improvement of the relationship among management, employees, customers and investors.
• Reduction in cost.

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ISO 14000 Series-

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National Accreditation Board for Testing and Calibration Laboratories
(NABL)-
-NABL is an autonomous constituent board of quality council of India.
-NABL stands for “National Accreditation Board for Testing and Calibration Laboratories”. -
NABL has been established and constituted for providing accreditation to the Government,
industry associations and individual industry or organizations.
-The accreditation is related to the third party assessment of the technical competence of testing
which includes medical and calibration laboratories, proficiency testing providers (PTP) and
reference material producers (RMP).

Benefits of NABL Accreditation-

NABL accreditation of drug testing laboratories has the following advantages:
1) Due to accreditation status, customer confidence in testing and calibration reports issued by
the laboratory has increased.
2) Due to enhanced customer confidence and satisfaction, the business of laboratory has also
increased.
3) Accreditation provides better control over the laboratory operations.
4) Laboratories get feedback about their technical capability and quality assurance system.
5) Database or directory of NABL accredited laboratories is made available both online and
offline. Customers can easily access NABL accredited laboratories for their specific
requirements.
6) NABL accreditation results in time and money saving as the need for retesting of the
products is reduced or eliminated.

Scope of NABL Accreditation-

NABL provides accreditation in the following fields and disciplines:
1) Testing laboratories,
2) Medical laboratories,
3) Proficiency testing providers, and
4) Calibration laboratories,
5) Reference material producers.

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The following fields/disciplines related to biopharmaceuticals are covered under the scope of
NABL accreditation:
1) Drugs and pharmaceuticals,
2) Cosmetics and essential oils,
3) Ayush products,
4) Plants and plant materials,
5) Cell culture,
6) Molecular analysis,
7) Resistance to microbial attack,
8) Toxicology,
9) Veterinary testing,
10) Biologicals derived pharmaceuticals,
11) Nutraceuticals,
12) Medical accessories and surgical products,
13) Medical laboratories including microbiology and serology, clinical biochemistry,
histopathology, cytopathology, clinical pathology, haematology and immune haematology,
genetics.
14) Inorganic and organic reference materials.

Good Laboratory Practice (GLP)-

-GLP is a set of rules, operating procedures and practices established by an organization to
ensure the quality and accurate results in a laboratory practice.
-In this practice, the organization sets the principles and the laboratory works are planned,
operated, overlooked and reported.
-The purpose of Good laboratory practice (GLP) :
.To promote the development of quality and validity of test data used for determining the
safety of chemicals, Pharmaceuticals, Food, Cosmetics etc.

SCOPE OF GLP-
-The term GLP applies to the non-clinical testing required for approval of new drug products
for human and animal use.

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-Its scope also extends to cover non-pharmaceutical compounds like food additives, colour
additives, food packaging, food contamination limits,biological products, electronic products
and medical devices.
-If a firm hires the services of a contract laboratory or a consultant laboratory service for the
testing, that laboratory must also abide by GLP.
-GLP does not cover human clinical studies.

General Provision-
-The GLP regulations set out rules for good practice and assist the researchers to work in
compliance with their own pre-established plans and standard procedures.
-The regulations neither include the scientific or technical content of the research programmes,
nor evaluate the scientific value of the studies.
-All GLP texts, regardless of their origin, state the importance of the following:
1) Resources: Organisation, personnel, facilities, and equipment.
2) Characterisation: Test items and test systems.
3) Rules: Study plans (or protocols) and written procedures.
4) Results: Raw data, final report, and archives.
5) Quality Assurance.

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