Pharmaceutical Sciences

PHARMACEUTICAL SCIENCES

Subject : Pharmaceutical Sciences

(For Under Graduate Students)

Paper No. : B. Pharm VIIIth Sem

Paper – 33
GMP, Quality Assurance & Validation

Topic No. & Title : 406 (A):

Concept of CGMP,
Total Quality Management

Academic Script

INTRODUCTION
Let's start with general introduction about Concept of CGMP and Total Quality
Management
CGMP refers to the Current Good Manufacturing Practice regulations enforced by the
US Food and Drug Administration (FDA). CGMPs provide for systems that assure
proper design, monitoring, and control of manufacturing processes and facilities.
Adherence to the CGMP regulations assures the identity, strength, quality, and purity
of drug products by requiring that manufacturers of medications adequately control
manufacturing operations. This includes establishing strong quality management
systems, obtaining appropriate quality raw materials, establishing robust operating
procedures, detecting and investigating product quality deviations, and maintaining
reliable testing laboratories. This formal system of controls at a pharmaceutical
company, if adequately put into practice, helps to prevent instances of
contamination, mix-ups, deviations, failures, and errors. This assures that drug
products meet their quality standards.

Total Quality Management (TQM) has three words: Total - made up of the whole;
Quality - degree of excellence a product or service provides; Management - act, art or
manner of planning, controlling, directing all the activities. Hence, TQM is the art of
managing the whole to achieve excellence. For successful implementing TQM it
needs ethics, integrity, trust, training, teamwork, leadership, recognition and
communication.

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CONCEPT OF CGMP
FDA regulates the quality of pharmaceuticals very carefully. The main regulatory
standard for ensuring pharmaceutical quality is the Current Good Manufacturing
Practice (CGMPs) regulation for human pharmaceuticals. Consumers expect that
each batch of medicines they take will meet quality standards so that they will be
safe and effective.

The CGMP requirements were established to be flexible in order to allow each

manufacturer to decide individually how to best implement the necessary controls by
using scientifically sound design, processing methods, and testing procedures. The
flexibility in these regulations allows companies to use modern technologies and
innovative approaches to achieve higher quality through continual improvement.
Accordingly, the "C" in CGMP stands for "current," requiring companies to use
technologies and systems that are up-to-date in order to comply with the
regulations. Systems and equipment that may have been "top-of-the-line" to prevent
contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by
today's standards.

It is important to note that CGMPs are minimum requirements. Many pharmaceutical

manufacturers are already implementing comprehensive, modern quality systems
and risk management approaches that exceed these minimum standards.

Good Manufacturing Practice (GMP)

It is the system of quality assurance aimed at ensuring that products are consistently
manufactured to a quality appropriate for their intended use. It is thus concerned
with both manufacturing and quality control processes and procedures.

Following are the basic GMP facility requirements that have to be followed by the
pharmaceutical manufacturers:
a) Manufacturing processes should be properly defined and controlled. All critical
processes should be validated to ensure consistency of the process. Results of
the validation of the processes should comply with specifications.
b) Batch Manufacturing Records should be controlled, and any changes to the
process should be evaluated. Changes that can have any impact on the quality
of the product must be validated.
c) Procedures and any instructions should be written in clear language to
understand the properly.
d) Personnel should be trained for production, quality control and to carry out
the documentation.

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e) At the time of production and testing of final products, the records made
manually or by instruments that provide the evidence that all the steps defined
in procedures and instructions were done properly. Any deviation from the
written procedure should be investigated and documented.
f) Documents of manufacturing including distribution with complete history of a
batch should be retained till expiry of the batch.
g) A well defined procedure should be available to recalling any batch from
market.
h) Market complaints of batches should be examined and the root causes of the
defects should be investigated and appropriate preventive action should be
taken to prevent recurrence of the defect.

Basic GMP Guidelines

1. Personnel
a. There shall be an adequate number of personnel at all levels having
knowledge, skills and capabilities relevant to their assigned functions, in
good mental and physical health to be able to execute their duties.
b. The organizational structure of the company shall be such that the
production and the quality assurance are headed by different managers,
neither of whom shall be responsible to the other.
c. All employees who are directly and indirectly engaged in the
manufacturing activities shall be trained in the particular operations that
the employees perform in accordance with the principles of Current Good
Manufacturing Practice.
d. Training shall be conducted by qualified individuals. Special attention shall
be given to training of personnel working in sterile and clean areas or with
highly potent, toxic or sensitizing materials.

2. Location, Layout and Design of Premises

a. The building(s) - factory shall be designed, constructed, adapted and
maintained to permit production of drugs under hygienic conditions
according to Factories Act, 1948
b. The premises for manufacturing shall be of suitable size, design,
construction and location to facilitate proper operation, cleaning and
maintenance.
c. The individual working areas shall be adequate so that any risk of confusion,
cross-contamination and other mistakes that will adversely affect the
quality of drugs and devices shall be avoided.

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d. Premises shall be constructed and maintained to protect against weather,

flood, ground seepage and the access and harboring of vermin, rodents,
birds, insects or other animals.
e. The layout of rooms, corridors, and spaces shall provide for logical
movements of materials and personnel with minimal traffic for operations
to be carried out in defined areas and to avoid cross contamination.
f. The design and layout of premises shall fulfil the following requirements:
the risk of mix-up between different drugs or their components, the
possibility of cross-contamination by other drugs or substances and the risk
of omission of any production step shall be prevented.
g. A plan of the building(s) showing air handling facilities including key air
handling equipment and showing air quality standards, flow rates,
proportions re-circulated and relative air pressures shall be made available
for inspection.
h. Should have proper water supply, warehousing facility, production area,
ancilliary area, waste management and all other facilities required.

3. Equipment
a. Equipment used in the manufacturing of drug products shall be of
appropriate design and construction, adequate size and suitably located in
order to assure product quality and process reproducibility and to facilitate
its cleaning and maintenance.
b. Equipment shall be subjected to regular maintenance checks at appropriate
intervals to prevent malfunctions.
c. Validation of equipments shall be conducted following a Validation
Protocol.
d. Heating, ventilation, air conditioning, potable water, purified water,
distilled water, clean steam, compressed air, gases and other support
systems must undergo validation.

4. Sanitation and Hygiene

a. High level of sanitation shall be practiced in every aspect of manufacturing
drug products.
b. It includes personnel, premises, equipment and apparatus, production
materials and containers and anything that could become a source of
contamination to the product.
c. Potential sources of contamination shall be eliminated through an
integrated comprehensive program of sanitation and hygiene.

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d. In all instances, the sanitation and the hygiene procedures should be

validated and periodically assessed to ensure that the effectiveness of the
operation meets the requirements.

5. Storage of Starting and Packaging Materials, Intermediates, Bulk Products

and Finished Products
a. Materials shall be stored in an orderly manner to prevent any risk of mix-
up or contamination and to facilitate inspection and maintenance.
b. Materials shall be stored under suitable environmental condition.
c. The First Expiry First Out system (FEFO) on approved raw materials shall be
used.

6. Production
a. Production shall follow defined procedures capable to provide assurance of
consistently yielding drug products that conform to their specifications.
b. There shall be a system describing the details of the batch and/or lot
numbering set up to ensure that each batch or lot of intermediate, bulk or
finished product is identified with a specific batch or lot number.
c. The methods for handling, weighing, counting and dispensing raw
materials, packaging materials, intermediate products, and bulk products
shall be included in written procedures.
d. All operation shall be performed in accordance with the written
procedures. Any deviation shall be justified and reported.

7. Packaging
a. The function of the packaging operation is to subdivide and control bulk
product. These operations shall be performed under strict control designed
to protect the identity, integrity and quality of the final package.
b. All packaging operations shall proceed in accordance with a Standard
Operating Procedures (SOP).

8. Finished Product Quarantine and Delivery to Warehouse

a. Finished product quarantine is the last point of control before the product
enters the warehouse and becomes available for distribution to the
market.
b. Strict controls shall be exercised to ensure that the product and its
packaging records meet all specified requirements before release to the
warehouse.

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9. Quality Control
a. Quality Control is an essential part of Good Manufacturing Practices to
provide assurance that the products will be consistently of a quality
appropriate to their intended use.
b. The involvement and commitment of all concerned at all stages are
mandatory towards the achievement of this quality objective from the start
of manufacturing to the distribution of the finished product. An independent
quality control unit shall be Established.

10.Documentation and Record Maintenance

a. Documentation in any manufacturing is a part of management information
system, which includes specifications, procedures, methods and instructions,
reports and records and other documents that are required for planning,
organizing, controlling and evaluating the whole activities of drug
manufacturing.
b. Documentation is essential for ensuring that each personnel receives clear
and detailed description of the relevant job assignment to minimize the risk
of misinterpretation and error, which are normally associated with habits of
communication by oral practice only.
c. A documentation system shall be designed such that a complete history of
each manufactured batch or lot of product can be traced back to enable
investigation of the batch or lot whenever it becomes necessary.
d. A documentation system is also required for monitoring and controlling the
condition of environment, equipment and personnel.
e. Must maintain following records
f. Standard Operating Procedures (SOPS) And Records, Regarding
i. Receipt of Materials
ii. Sampling
iii. Batch Numbering
iv. Testing
v. Records of analysis.
g. Master Formula Records
h. Batch Processing Records
i. Quality Control records
j. Batch Packaging Records
k. Packaging Records
l. Distribution Records
m. Complaints Records

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11.Product Containers and Closures

All containers & closures intended for use shall comply with the
pharmacopoeial requirements. Whenever bottles are being used, the written
schedule of cleaning shall be laid down and followed. Where bottles are not
dried after washing, they should be rinsed with de-ionized water or distilled
water.

12.Complaints and Recalls

All quality related complaints, whether received orally or in writing, should be
recorded and investigated according to a written procedure. Records of
complaints should be retained in order to evaluate trends, product-related
frequencies, and severity with a view to taking additional, and if appropriate,
immediate corrective action.

TOTAL QUALITY MANAGEMENT (TQM)

TQM is a management philosophy that seeks to integrate all organizational functions
(marketing, finance, design, engineering, and production, customer service, etc.) to
focus on meeting customer needs and organizational objectives. A core definition of
total quality management (TQM) describes a management approach to long–term
success through customer satisfaction. In a TQM effort, all members of an
organization participate in improving processes, products, services, and the culture in
which they work.

TQM views an organization as a collection of processes. It maintains that

organizations must strive to continuously improve these processes by incorporating
the knowledge and experiences of workers. The simple objective of TQM is “Do the
right things, right the first time, every time.” TQM is infinitely variable and adaptable.
Although originally applied to manufacturing operations, TQM is now becoming
recognized as a generic management tool, just as applicable in service and public
sector organizations. There are a number of evolutionary strands, with different
sectors creating their own versions from the common ancestor. TQM is the
foundation for activities, which include:
a) Commitment by senior management and all employees
b) Meeting customer requirements
c) Reducing development cycle times
d) Just in time/demand flow manufacturing
e) Improvement teams
f) Reducing product and service costs
g) Systems to facilitate improvement

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h) Line management ownership

i) Employee involvement and empowerment
j) Recognition and celebration
k) Challenging quantified goals and benchmarking
l) Focus on processes / improvement plans
m) Specific incorporation in strategic planning

This shows that TQM must be practiced in all activities, by all personnel, in
manufacturing, marketing, engineering, R&D, sales, purchasing, HR, etc.

Advantages of TQM
The benefits of TQM could be well understood by following comparisons:

Table 1: Organizational Cultural Change before and after adopting TQM

Traditional Approach TQM
Lack of communication Open communications
Control of staff Empowerment
Inspection & fire fighting Prevention
Internal focus on rule External focus on customer
Stability seeking Continuous improvement
Adversarial relations Co-operative relations
Allocating blame Solving problems at their roots

Table 2: Improvement after TQM as compared to traditional approach

Traditional Approach Continuous Improvement after
TQM
Market-share focus Customer focus
Individuals Cross-functional teams
Focus on ‘who” and “why” Focus on “what” and “how”
Short-term focus Long-term focus
Status quo focus Continuous improvement
Product focus Process improvement focus
Innovation Incremental improvements
Fire fighting Problem solving

Benefits of Introducing TQM

The most important benefits of introducing TQM into a company are the following:
a) It makes the company focus clearly on the needs of its market. This is essential
for a company to survive in the competitive market.

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b) It helps in achieving a top quality performance in all areas, not only in the final
product or service quality. In fact, achieving top quality performance in all
areas reflects substantially on the final product or service quality, since quality
is a continuous chain.
c) It assists in implementing the simple procedures necessary for the
achievement of quality performance.
d) It helps, critically and continuously, in examining all processes to remove non-
productive activities and waste.
e) It determines the required improvements and develops a measure of
performance.
f) It provides full, detailed understanding of the competition and develops an
effective competitive strategy.
g) It develops the team approach to problem solving.
h) It develops good procedures for communication and recognition of
outstanding work.
i) It reviews continuously the processes to develop the strategy of never ending
improvement
j) Management objectives, such as customer satisfaction, meeting specifications,
larger market share, higher productivity, zero defects, increase in sale and
decrease in costs, can be achieved by embodying TQM ethics in all aspects of
the organization.

Principles of TQM
The key principles of TQM are as following:
1) Management Commitment
a. Plan (drive, direct)
b. Do (deploy, support, participate)
c. Check (review)
d. Act (recognize, communicate, revise)
2) Employee Empowerment
a. Training
b. Suggestion scheme
c. Measurement and recognition
d. Excellence teams
3) Fact Based Decision Making
a. SPC (statistical process control)
b. DOE, FMEA
c. The 7 statistical tools
d. TOPS (Ford 8D – team-oriented problem solving)

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4) Continuous Improvement
a. Systematic measurement and focus on CONQ
b. Excellence teams
c. Cross-functional process management
d. Attain, maintain, improve standards
5) Customer Focus
a. Supplier partnership
b. Service relationship with internal customers
c. Never compromise quality
d. Customer driven standards

Total Quality Management (TQM) is a comprehensive and structured approach to

organizational management that seeks to improve the quality of products and
services through ongoing refinements in response to continuous feedback. TQM
requirements may be defined separately for a particular organization or may be in
adherence to established standards, such as the International Organization for
Standardization's ISO 9000 series. TQM can be applied to any type of organization; it
originated in the manufacturing sector and has since been adapted for use in almost
every type of organization imaginable, including schools, highway maintenance, hotel
management, and churches. As a current focus of e-business, TQM is based on
quality management from the customer's point of view.
Quality achievement, according to Juran, is possible through various initiatives that
are the basis of his famous quality trilogy the main components of which are:
a) Quality planning
b) Quality control and
c) Quality improvement

The three aspects of TQM

a) Counting: Tools, techniques, and training in their use for analyzing,
understanding, and solving quality problems.
b) Customers: Quality for the customer as a driving force and central concern.
c) Culture: Shared values and beliefs, expressed by leaders, that define and
support quality.
W. Edwards Deming’s 14 Points for TQM
a) Create constancy of purpose towards improvement of product and services.
b) Adopt the new philosophy. We can no longer live with commonly accepted
levels of delays, mistakes, defective workmanship.
c) Cease dependence on mass inspection. Require, instead, statistical
evidence that quality is built in.

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d) End the practice of awarding business on the basis of price tag.

e) Find problems. It is management’s job to work continually on the system.
f) Institute modern methods of training on the job.
g) Institute modern methods of supervision of production workers. The
responsibility of foremen must be changed from numbers to quality.
h) Drive out fear that everyone may work effectively for the company.
i) Break down barriers between departments.
j) Eliminate numerical goals, posters and slogans for the workforce asking for
new levels of productivity without providing methods.
k) Eliminate work standards that prescribe numerical quotas.
l) Remove barriers that stand between the hourly worker and his right to
pride of workmanship.
m) Institute a vigorous programme of education and retraining.
n) Create a structure in top management that will push everyday on the above
13 points.

TQM Six Basic Concepts

a) Leadership
b) Customer Satisfaction
c) Employee Involvement
d) Continuous Process Improvement
e) Supplier Partnership
f) Performance Measures

People
Culture Communication
s

Systems Processes
Commitment

Fig. 02: Building blocks of TQM

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TQM processes
TQM processes are divided into four sequential categories: plan, do, check, and act
(the PDCA cycle).
a) In the planning phase, people define the problem to be addressed, collect
relevant data, and ascertain the problem's root cause;
b) In the doing phase, people develop and implement a solution, and decide upon
a measurement to gauge its effectiveness;
c) In the checking phase, people confirm the results through before-and-after
data comparison;
d) In the acting phase, people document their results, inform others about
process changes, and make recommendations for the problem to be addressed
in the next PDCA cycle.

PDCA (plan–do–check–act or plan–do–check–adjust) is an iterative four-step

management method used in business for the control and continuous improvement
of processes and products. It is also known as the Deming circle/cycle/wheel, She
whart cycle, control circle/cycle, or plan–do–study–act (PDSA). Another version of
this PDCA cycle is OPDCA. The added "O" stands for observation or as some versions
say "Grasp the current condition." This emphasis on observation and current
condition has currency with Lean manufacturing/Toyota Production System
literature.

Fig. 02: Plan Do Check Act ( PDCA) Cycle

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Hurdles for Implementing TQM

a) Lack of a customer focus.
b) Lack of a company-wide definition of quality.
c) Lack of a formalized strategic plan for change.
d) Poor inter-organizational communication.
e) Lack of real employee empowerment.
f) Lack of employee trust in senior management.
g) View of the quality program as a quick fix.
h) Drive for short-term financial results.
i) Politics and turf issues.

Table 3. Reasons for TQM failure (Brown, et al 1994)

No. Phase Reasons for TQM failure
I. Start-up a) Lack of management commitment
b) Poor training and pacing
c) Wasted education and training
d) Lack of short-term, bottom line result.
II. Alignment a) Divergent strategies
b) Inappropriate measures
c) Outdated appraisal methods
d) Inappropriate rewards
III. Integration a) Failing to transfer true power to employees
b) Maintaining outmoded management
practices
c) Poor organization and job design
d) Outdated business systems

CONCLUSION
With all these information here we come to end of today's lecture. Hope we have
understood the details related to the above discussed two topics. Further have a look
again on the complete topic yourself so that you are thorough with it.

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