Showing posts with label Pharmaceutical Process. Show all posts
Showing posts with label Pharmaceutical Process. Show all posts

Quality Pioneers and their key Contributions

Definitions of Quality:

1. The degree to which a set of inherent properties of a product, system or process fulfils requirements. (ICH Q9)  

2. The degree to which a set of inherent characteristics fulfill requirements - ISO 9000 

3. A degree of excellence – The Concise Oxford Dictionary 

4. Fitness for use – Joseph Juran 

5. Quality is a dynamic state associated with products, services, people, processes, and environments that meets or exceeds expectations and helps produce superior value – Goetsch and Davis (2010) 

6. Conformance to requirements – Phil B. Crosby (1979) 

Top most popular Quality Gurus:

1. Joseph Juran (December 24, 1904 – February 28, 2008):

Joseph Moses Juran known as the "father" of modern-day Quality management. He was a Romanian-born American engineer.

His contribution to society:

Joseph Juran was a management consultant specialising in managing quality. He has authored nos. of papers and 12 books, including famous book of Juran's Quality control handbook, Quality Planning and Analysis, and Juran on Leadership for Quality.

Pareto principle:

Vilfredo Pareto was an Italian economist who observed that 80% of the effects come from 20% of the causes. Juran applied his observations to business management and economics.

Juran's Trilogy:

It is an approach to cross-functional management composed of following three managerial processes:

1. Quality Planning

Quality Planning is the activity of developing the products and processes required to meet customers' needs.

2. Quality Control

Quality Control is the activity of monitoring production activities to ensure that they are producing the correct product or service according to plan.

3. Quality Improvement

Quality Improvement is the activity of making changes to improve the process and raising quality performance to extraordinary levels.

Cost of quality

The cost of quality (or the cost of not getting it right the first time) should be recorded and analysed.

Quality Improvement 

Ten steps to quality improvement are…

1. Build awareness of the need and opportunity to improve

2. Set goals for that improvement

3. Create plans to reach the goals

4. Provide training

5. Conduct projects to solve problems

6. Report on progress

7. Give recognition for success

8. Communicate results

9. Keep score

10. Maintain momentum

2. William Edwards Deming (October 14, 1900 – December 20, 1993):

Edwards Deming was an American engineer, statistician, professor, author, lecturer, and management consultant. Educated initially as an electrical engineer and later specializing in mathematical physics, he helped develop the sampling techniques still used by the U.S. Department of the Census and the Bureau of Labour Statistics.

His contribution to society:

The Deming Cycle - PDCA

PDCA (Plan-Do-Check-Act) is an iterative four-step management method used in business to control and continuously improve processes and products.

1. Plan

Plan the action. Assess the current and future state, and plan how to close the gap. Identify alternate solutions.

2. Do

Try out or test the solutions (sometimes at a pilot level).

3. Check

Check to see if the tested solutions accomplished the objective.

4. Act

Analyse the difference between actual and planned results. If the gap is significant, determine the root cause and request corrective action.

Deming's fourteen points for Total Quality Management include:

1. Create constancy of purpose

Create constancy of purpose toward improvement of product and service, with the aim to become competitive, stay in business, and provide jobs.

2. Adopt the new philosophy

Adopt the new philosophy. We are in a new economic age. Western management must awaken to the challenge, learn their responsibilities, and take on leadership for change.

3. Cease dependence on inspection

Cease dependence on inspection to achieve quality. Eliminate the need for inspection on a mass basis by building quality into the product in the first place.

4. End the practice of awarding business on the basis of price tag

End the practice of awarding business on the basis of the price tag. Instead, minimize total cost. Move toward a single supplier for any one item, on a long-term relationship of loyalty and trust.

5. Improve constantly

Improve constantly and forever the system of production and service to improve quality and productivity, thus constantly decreasing costs.

6. Institute training

Institute training on the job.

7. Institute leadership

The aim of supervision should be to help people and machines and gadgets to do a better job. Supervision of management needs an overhaul, as well as supervision of production workers.

8. Drive out fear

Drive out fear so that everyone may work effectively for the company.

9. Break down barriers

Break down barriers between departments. People in research, design, sales, and production must work as a team to foresee problems of production and in use that may be encountered with the product or service.

10. Eliminate slogans, exhortations, and targets

Eliminate work standards (quotas) on the factory floor.

Eliminate management by objective. Eliminate management by numbers and numerical goals. 

11. Pride of workmanship

Remove barriers that rob the hourly worker of his right to pride in workmanship. The responsibility of supervisors must be changed from sheer numbers to quality.

12. Abolishment of the annual or merit rating

Remove barriers that rob people in management and engineering of their right to pride in workmanship. This means, among other things, abolishing the annual or merit rating and Management by Objectives.

13. Education and self-improvement

Institute a vigorous program of education and self-improvement.

14. Transformation

Put everybody in the company to work to accomplish the transformation. Transformation is everybody's job.

3. Kaoru Ishikawa (July 13, 1915 – April 16, 1989):

Kaoru Ishikawa was a Japanese organizational theorist and a professor in the engineering faculty at the University of Tokyo noted for his quality management innovations. 

He is considered a key figure in the development of quality initiatives in Japan, particularly the quality circle. 

He is best known outside Japan for the Ishikawa or cause and effect diagram (also known as the fishbone diagram), often used in the analysis of industrial processes.

He wrote 647 articles and 31 books, including two translated into English: "Introduction to Quality Control" and "What Is Total Quality Control?

His contribution to society:

Ishikawa Diagram:

The Ishikawa Diagram is also called the Fishbone diagram and the Cause-and-Effect-Analysis. This is the most commonly used to analyse a problem and to find out the potential causes creating the problem.

Quality Circles

Quality Circle is a small group of employees working in the same area or doing the same job. This group regularly meets for one hour every week to identify and collectively resolve the problems in the work area. They use Seven Basic Quality tools to understand the causes and propose solutions.

Seven Basic Quality Tools:

1. Flow charts (Also called as Stratification or Run Chart)

2. Scatter diagrams

3. Pareto Charts

4. Histogram

5. Check sheets

6. Cause and Effect Diagram

7. Control charts

Company-wide Quality Control

He emphasized the concept of internal customers and Company-wide Quality. This requires the involvement of all, from the top management to the front-line workers. He suggested the following benefits of the Company-wide Quality approach.

  • Reduced defects
  • Improved product quality
  • The quality improvement becomes the norm rather than the exception
  • Increased reliability
  • Reduced costs
  • Wastes are identified and reduced
  • Rework is identified and reduced
  • Improvement techniques are established, and the product and processes are continually improved
  • Inspection and after-the-fact expenses are reduced
  • Sales and market opportunities are increased
  • Company reputation is increased
  • Interdepartmental barriers are broken down, and communication becomes easier
  • False and inaccurate data is reduced
  • Improvement in human relations
  • Company loyalty is increased

4. Walter Shewhart (March 18, 1891- March 11, 1967):

Walter Andrew Shewhart was an American physicist engineer and statistician, sometimes known as the father of statistical quality control.

He also lectured on quality control and applied statistics at the University of London, Stevens Institute of Technology, the graduate school of the U.S. Department of Agriculture, and in India.

His contribution to society:

Control Charts

Control charts are also known as Shewhart charts (after Walter A. Shewhart ).

Shewhart classified the causes of variation as "assignable cause" and "chance cause".

PDCA Cycle

The original founder of the PDCA cycle (Plan-Do-Check-Act) is Walter A. Shewhart.  Edwards Deming promoted the use of the PDCA cycle for process improvement and later changed it to the PDSA cycle (Plan-Do-Study-Act).

5. Philip Crosby (Jun 18, 1926- Aug 18, 2006):

Crosby is founder and chairman of the board of Career IV, an executive management consulting firm. Crosby also founded Philip Crosby Associates Inc. and the Quality College. He has authored many books, including Quality is free, Quality without tears, Let's talk Quality, and Leading: The art of becoming an executive. Crosby originated the concept of zero defects.

His contribution to society:

Crosby give principle "doing it right the first time"

The Crosby Vaccine

In the Crosby style, the "Vaccine" is explained as medicine for management to prevent poor quality. It is in five sections that cover the requirements of Total Quality Management.

Integrity

Treat quality seriously throughout the whole business organization from top to bottom. The company's future will be judged on its performance on quality.

Systems

Appropriate measures and systems should be put in place for quality costs, education, quality, performance, review, improvement and customer satisfaction.

Communication

The communication systems are of paramount importance to communicate requirements and specifications and improvement opportunities around the organization. Customers and operators know what needs to be put in place to improve, and listening to them will give you the edge.

Operations

Work with and develop suppliers. Processes should be capable, and improvement culture should be the norm.

Policies

Policies must be clear and consistent throughout the business.

The Fourteen Steps to Quality Improvement

1. Management Commitment

Make it clear that management is committed to quality.

2. Quality Improvement Teams

Form Quality Improvement Teams with senior representatives from each department.

3. Measure Processes

Measure processes to determine where current and potential quality problems lie.

4. Cost of Quality

Evaluate the cost of quality and explain its use as a management tool.

5. Quality Awareness

Raise the quality awareness and personal concern of all employees.

6. Correct Problems

Take actions to correct problems identified through previous steps.

7. Monitor Progress

Establish progress monitoring for the improvement process.

8. Train Supervisors

Train supervisors to actively carry out their part of the quality improvement program.

9. Zero Defects Day

Hold a Zero Defects Day to reaffirm management commitment.

10. Establish Improvement Goals

Encourage individuals to establish improvement goals for themselves and their group.

11. Remove Fear

Encourage employees to tell management about obstacles to improving quality.

12. Recognize

Recognize and appreciate those who participate.

13. Quality Councils

Establish Quality Councils to communicate on a regular basis.

14. Repeat the Cycle

Do it all over again to emphasize that the quality improvement process never ends.

Apart of above quality gurus, following Quality gurus are also  contributed in society to many quality tools for improvement of product quality.

1. Shigeo Shingo (1909-1990):

He is best known for “Poka-yoke” is a Japanese term that means “mistake-proofing”.

2. Taiichi Ohno (1912-1990):

He is best known for “Toyota Production System” and “Seven types of wastes (Muda)”.

3. Genichi Taguchi (Jan 1, 1924-June 2, 2012):

Genichi Taguchi is best known for:

Taguchi Methods

Taguchi Loss Function

Design of Experiments

Robust Design

Quality Engineering

4. Armand Feigenbaum (1922-2014):

Feigenbaum is best known for:

Total Quality Control

Hidden Plant

Quality Costs


About the Author:
Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance. 
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer: The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.

History of Sterility Test

When Sterility Test mandated in regulatory

In the British Pharmacopoeia sterility testing was first mandated in 1932 however, before this there were other regulations for specific tests and products specified under the Therapeutic Substances Act.

The WHO were adopted requirement of sterility in 1973.

Sterility testing is absolutely essential for safe pharmaceutical & medical devices. The sterility test assesses whether or not the products contain microbiological contamination, which could be harmful in human health.

What is sterility? 

Sterility can be defined as the freedom from the presence of viable microorganisms. 

Flow of sterility test: 

Media for Sterility testing:

1. Fluid Thioglycollate Medium (FTM):

It is primarily intended for the culture of anaerobic bacteria. However, it will also detect aerobic bacteria.

2. Soybean–Casein Digest Medium (SCDM):

Soybean-Casein Digest Medium is suitable for the culture of both fungi and aerobic bacteria.

Sterility Test Methods:

Sterility test methods mentioned in USP <71> “Sterility Test”. 

The three methods of Sterility Testing are membrane filtration, Direct Transfer (Product Immersion) and Product Flush.

1. Membrane Filtration Method for Sterility Testing

The Membrane Filtration Sterility Test is the method of choice for pharmaceutical products. An appropriate use of this test is for devices that contain a preservative and are bacteriostatic and fungistatic under the direct transfer method. 

With membrane filtration, the concept is that the microorganisms will collect onto the surface of a sub-micron pore size filter. This filter is segmented and transferred to appropriate media. The test media are fluid thioglycollate medium (FTM) and soybean casein digest medium (SCDM) and incubated for 14 days.

2. Direct Transfer Sterility Testing

This method is the method of choice for medical devices because the device is in direct contact with test media throughout the incubation period. 

Viable microorganisms that may remain in or on a product after sterilization have an ideal environment within which to grow and proliferate. 

This is especially true with damaged microorganisms where the damage is due to a sub-lethal sterilization process. 

All microorganisms have biological repair mechanisms that can take advantage of environmental conditions conducive to growth. The direct transfer method benefits these damaged microorganisms. The entire product should be immersed in test fluid. With large devices, patient contact areas should be immersed. 

The method requires that the product be transferred to separate containers of both FTM and SCDM. 

The product is aseptically cut, or transferred whole, into the media containers. After being transferred, the samples are incubated for 14 days.

3. Product Flush Sterility Testing

The product flush sterility test is reserved for products that have hollow tubes such as transfusion and infusion assemblies where immersion is impractical and where the fluid pathway is labelled as sterile. 

The products are flushed with fluid and the eluate is membrane filtered and placed into FTM and SCDM.

What science behind 14 days incubation time for Sterility test?

Often bacteria require 3-5 days for the growth and fungus require 5-7 days for growth but sterility testing require 14 days of long incubation time because of following two reasons.

1.    There are some bacteria which are very slow growing like Propionibacterium acne. P.acne is gram positive, rod shaped, slow growing bacteria which is found in the acne of humans. This bacterium is very slow growing, and it could be the source of product contamination. To recover these type of slow growing microorganisms, 14 days are enough to support the growth of these microorganisms if present in the product. 

2. In aseptic environment microorganisms could be in damaged or in injured form so, it requires long time for the recovery of these microorganisms in media. That's why sterility testing require 14 days of long incubation time.

Bulk Drug Products / Biologics and Pharmaceuticals:

Bulk Pharmaceuticals (APIs) are tested for sterility as per USP <71> before release to the manufacturing processes. Bulk Biologics are tested according to 21 CFR 610.12 for sterility testing. This method requires one media (FTM).

NEW Amendments to Sterility Test Requirements for Biological Products Final Rule – 21 CFR Parts 600, 610, and 680.

FDA issues Final Rule on sterility testing of biological products providing greater flexibility for development of sterility test methods. The purpose of the amendments are as follows:

Promote improvement and innovation in the development of sterility test methods.

Address the challenges of novel products that may be introduced to the market in the future.

Potentially enhance sterility testing of currently approved products.

Suitability and Validation:

The USP Sterility Test contains two qualifying assays which must be performed. They are the following. 

1. Suitability Test (Growth Promotion Test) 

The Suitability Test is used to confirm that each lot of growth media used in the sterility test procedure will support the growth of fewer than 100 viable microorganisms. 

If the media cannot support the growth of the indicator organisms, then the test fails. Secondly, a portion of each media lot must be incubated and assessed for sterility according to the incubation parameters established by the method. If the media is found to be non-sterile, then the test fails.

2. Validation Test (Bacteriostasis and Fungistasis Test)

The Validation Test is used to determine if the test sample will inhibit the growth of microorganisms in the test media. 

Stasis, in terms of microbiology, is defined as the inability of a microorganism to grow and proliferate in microbiological media. Media that is bacteriostatic does not necessarily kill bacteria; it may simply inhibit bacterial growth and proliferation. 

The Validation Test must be performed on each product prior to and/or during sterility testing. This test determines if the media volumes are valid for the particular product. Some medical products contain bacteriostatic and fungistatic compounds that may require special procedures and special media for testing. 

This test is similar to the Suitability Test described above, however, the product sample is placed in the media along with the microorganisms. Microbial growth in the presence of the test samples is compared to controls without test samples. 

If microbial growth is present in the sample and control containers, the test is valid. Suitability, validation and sterility tests can be performed simultaneously.

Observation and interpretation of results:

At intervals during the incubation period and at its conclusion, examine the media for macroscopic evidence of microbial growth. 

If the material being tested renders the medium turbid so that the presence or absence of microbial growth cannot be readily determined by visual examination, 14 days after the beginning of incubation transfer portions (each not less than 1 mL) of the medium to fresh vessels of the same medium, and then incubate the original and transfer vessels for not less than 4 days. 

If no evidence of microbial growth is found, the product to be examined complies with the test for sterility. If evidence of microbial growth is found, the product to be examined does not comply with the test for sterility, unless it can be clearly demonstrated that the test was invalid for causes unrelated to the product to be examined. 

The test may be considered invalid only if one or more of the following conditions are fulfilled: 

1. The data of the microbiological monitoring of the sterility testing facility show a fault. 

2. A review of the testing procedure used during the test in question reveals a fault. 

3. Microbial growth is found in the negative controls. 

4. After determination of the identity of the microorganisms isolated from the test, the growth of this species (or these species) may be ascribed unequivocally to faults with respect to the material and or the technique used in conducting the sterility test procedure.

If the test is declared to be invalid, it is repeated with the same number of units as in the original test. If no evidence of microbial growth is found in the repeat test, the product examined complies with the test for sterility. If microbial growth is found in the repeat test, the product examined does not comply with the test for sterility.

Investigating a Sterility Test Failure:

Investigating a Sterility Test Failure Whenever a sterility positive occurs, lab supervisors are responsible for starting the investigation immediately. Following factors should be evaluated in the basic investigation:

1. Equipment: 

Determine whether equipment malfunctioned or was not operated properly. If a malfunction occurred, determine whether it was likely to cause the contamination. Determine if any checklists or logs indicate that the ISO 5 device was in good state of repair at the time of the sterility test. Be aware of the most likely failure modes in the equipment (e.g., laminar flow hood, glovebox, or isolator) used.

2. Adherence to Analytical Method: 

Determine whether there were any anomalies or deviations from the analytical method. Adherence to method should be verified at the time of analysis, and any major breach of sterility test procedure should also be documented at that time. If any method breaches occurred, determine whether it was likely to cause the contamination. Be aware of any possible weaknesses in the test method (e.g., kit, manifold, etc.) used.

3. Analyst: 

Evaluate the analyst’s qualifications, including proficiency, training record, and experience. Also note whether the sterility testing practice of the analyst was observed during this or a recent analysis.

4. Cleanroom and ISO 5 (Class 100) Environmental Conditions:

Determine if disinfection/decontamination of the ISO 5 device was properly done. Determine whether there was adverse environmental data. Note that a negative control failure, on its own, is not necessarily cause for invalidating a result.

If a negative control was contaminated, consider whether the microbe identified is similar to, or the same as, the sterility test isolate and also consider whether there are other adverse environmental trends.

If an investigation finds that the conduct of the analysis included errors or events that caused the test specimens to be contaminated by the lab environment, the Sterility Test result would be invalid and the substandard laboratory practice should be corrected to prevent this problem from recurring.

Reference: 

1. USP <71> Sterility Tests.

2. 21 CFR Parts 600, 610, and 680.

3. PIC/S “Recommendation on sterility testing”

About the Author:

Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance. 
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer: The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.

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Challenges for current pharmaceutical companies

    As we all witness during COVID 19, supply of all necessity medicines was disturbed and all countries made their boundaries for import and export. Which were major impact on pharmaceutical supply and revenue.

   Now, after 2021 supply of all medicine and medical devices is on track, but somehow still this sector is facing some current issue nowadays which are following.

1. Required qualified workforce

➡️ Investment in pharmaceutical industries has been growing day by day after COVID 19. More investors are attract to this pharmaceutical field and make their own small manufacturing units and give competition to bigger and old players in the market.

➡️ Nos. of qualified workforce required to new under develop small pharmaceutical industries and need to train them properly on daily basis and fill the skill gaps in current industries.

➡️ So, this is one of the challenge for industries to improve company’s productivity with high grade quality.

➡️ Indeed, the more properly trained the staff, the more productive they become and reduce the gaps in the routine process.

2. Data collection and statistical evaluation

➡️ Now, pharmaceutical industries come in industry 4.0 and it's time for statistical data analysis and comes out for decision.

➡️ Nowadays, data gathering is a one of the crucial parts for every growing industry and make a stand in current competition.

➡️ After approval of pharmaceutical industries drug products in regulatory, data collection to be start from manufacturing, quality control and other maintenance services etc. This data collection is one of digitalized movement of industry and applied different statistic tools on collected data for taking proper assessment and focus on customer satisfaction.

➡️ Use well developed and regulatory approved statistical data evaluation software for routine data collection and take a preventive action during the manufacturing stage for improving product quality.

3. Supply chain disturbance

➡️ Currently, every industry is facing supply chain problems. Supply chains have witnessed an unprecedented disruption all around the world. In fact, this denotes one the major challenges facing the pharmaceutical industry.

➡️ Even though pharmaceutical company managers constantly seek to improve processes for maximum efficiency, technical contingencies might unfortunately cause a delay in the entire sector. Hence, to reduce the challenges of their pharmaceutical supply chain, they change their strategy and make the best use of their resources.

➡️ Even though we are in the midst of a global digital era, it is important that companies invest in monitoring software to improve efficiency. In fact, the monitoring software will help you see where your products are and the supply chain status. It also helps to predict potential problems. The software will also play a role in improving accountability and will help to avoid counterfeit products to be marketed.

4. Difficulties to manage brand against rising consumer expectation

➡️ Pharmaceutical frauds may major role to demonize brand values of giant pharmaceutical players.

➡️ This industry is under major scrutiny from customers and manage brand value may be more important than other tasks and At the same time, consumers are expecting more from the pharmaceutical industry.

➡️ Pharmaceutical companies will need to manage growing consumer expectations and be prepared to respond to brand crises throughout the year.

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About the Author:
Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance. 
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer:
The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.

Six sigma - A brief introduction

What is Six sigma?

➡️ Six Sigma is a set of tools and techniques to increase customer satisfaction and profitability by streamlining operations, improving quality and eliminating defects in every organization wide process.
➡️ It’s Greek symbol "sigma" or "σ," a statistical term for measuring process variable from the process mean or target. "Six Sigma" comes from the bell curve used in statistics. 

Who developed six sigma?

➡️ An American engineer Bill Smith working at Motorola company in 1986.

What are the benefits for using six sigma tools and techniques? 

  • Increasing Customer Satisfaction
  • Reducing Process Variability
  • Improving Processes
  • Lowering Defects
  • Reducing Costs
  • Increasing Profit

Sigma level vs percentage yield:

➡️ A six sigma process is a process that produces 3.4 defective parts per million opportunities (DPMO). 
➡️ Product percentage yield is directly proportional to sigma level. If sigma level is increase then percentage yield of product is increase and percentage of product defects reduce. See the following table for more details. 
Sigma levelDPMOPercent defectivePercentage yield
 1 691462 69% 31%
 2 308538 31% 69%
 3 66807 6.7% 93.3%
 4 6210 0.62% 99.38%
 5 233 0.023% 99.977%
 6 3.4 0.00034% 99.99966%
 7 0.019 0.0000019% 99.9999981%
➡️ If the process improvements do not reach 6 sigma, the improvements made from 3 sigma to 4 sigma to 5 sigma will still reduce costs and increase customer satisfaction.

The core Six Sigma principles:

➡️ Success of Six Sigma implementation is based upon following main principles:
  • Always focus on the customer.
  • Understand how work really happens.
  • Make your processes flow smoothly.
  • Reduce waste and concentrate on value.
  • Stop defects through removing variation.
  • Get buy-in from the team through collaboration.
  • Make your efforts systematic and scientific.

The Six Sigma Methodology:

➡️ The two main Six Sigma methodologies are DMAIC and DMADV. Each has its own set of recommended procedures to be implemented for business transformation.
1. DMAIC is a data-driven method used to improve existing products or services for better customer satisfaction. 
➡️ It is the acronym for the five phases:
D – Define
M – Measure
A – Analyse
I – Improve
C – Control
➡️ DMAIC is applied in the manufacturing of a product or delivery of a service.
2. DMADV is a part of the Design for Six Sigma (DFSS) process used to design or re-design different processes of product manufacturing or service delivery.
➡️ The five phases of DMADV are: 
D – Define
M – Measure
A – Analyse
D – Design
V – Validate
➡️ DMADV is employed when existing processes do not meet customer conditions, even after optimization, or when it is required to develop new methods.
➡️ If you wish to know more about difference in details of DMAIC and DMADV, put your comment in comment section. So, I will be prepared and explained the same in next article. 

Six Sigma Techniques:

➡️ The Six Sigma methodology also uses a mix of statistical and data analysis tools and proven qualitative and quantitative techniques, to achieve the desired outcome.
Voice of the Customer:
➡️ It used in the "define" phase of the DMAIC cycle.
➡️ This is the process used to capture the "voice of the customer" or customer feedback by either internal or external means.
Root Cause Analysis/The 5 Whys:
➡️ It used in the "analyze" phase of the DMAIC cycle.
➡️ In the 5 Whys technique, the question "why" is asked, again and again, finally leading up to the core issue.
Brainstorming:
➡️ It used in the "improve" phase of the DMAIC cycle.
➡️ Brainstorming involves bouncing ideas and generating creative ways to approach a problem through intensive freewheeling group discussions.
The 5S System:
This technique is Japanese principle of workplace energies. The 5S System is aimed at removing waste and eliminating bottlenecks from inefficient tools, equipment, or resources in the workplace. 
➡️ The five steps used are Seiri (Sort), Seiton (Set In Order), Seiso (Shine), Seiketsu (Standardize), and Shitsuke (Sustain).
Kaizen (Continuous Improvement):
➡️ The Kaizen technique is a powerful strategy that powers a continuous engine for business improvement. It is the practice continuously monitoring, identifying, and executing improvements.  
➡️ Collective and ongoing improvements ensure a reduction in waste, as well as immediate change whenever the smallest inefficiency is observed.
Poka-yoke (Mistake Proofing):
➡️ This technique's name comes from the Japanese phrase meaning "to avoid errors," and entails preventing the chance of mistakes from occurring. 
➡️ In the poka-yoke technique, employees spot and remove inefficiencies and human errors during the manufacturing process.
Benchmarking:
➡️ It involves making comparisons with other businesses to gain an independent appraisal of the given situation.
➡️ Benchmarking may involve comparing important processes or departments within a business (internal benchmarking), comparing similar work areas or functions with industry leaders (functional benchmarking), or comparing similar products and services with that of competitors (competitive benchmarking).
Value Stream Mapping:
➡️ The objective is to remove waste and inefficiencies in the value stream and create leaner operations. 
➡️ It identifies seven different types of waste and three types of waste removal operations.

What are the tools of Six Sigma? 

➡️ Following are list of tools often used during product improvement. 
Cause and Effect Analysis
Flow Chart
Pareto Chart
Histogram
Check Sheet
Scatter Plot
Control Chart

What are the Sigma levels? 

➡️ Based on knowledge, experience, training and eligibility, sigma level classified as white belt, yellow belt, green belt, black belta and master black belt. 
About the Author:
Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance. 
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer:
The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.

Lyophilization or Freeze Drying


Differences between Lyophilization and Freeze Drying? 

➡️ Lyophilization and freeze drying are terms that are used interchangeably depending on the industry and location where the drying is taking place. 
➡️ Hence, we use the term Lyophilization in this article. 

What is Lyophilization? 

➡️ It is a drying process that allows to preserve the original structure and characteristics of a drug product which is sensitive to heat.
➡️ The process of lyophilization was discovered in 1906 by the Frenchmen Arsène d'ARSONVAL and F. BORDAS, researcher of the Collège de France. 

How to work Lyophilization?

➡️ The fundamental principle in lyophilization is sublimation, the shift from a solid directly into a gas. Just like evaporation of liquid to gas, sublimation occurs when a molecule gains enough energy to break free from the molecules around it. Water will sublime from a solid (ice) to a gas (vapor) when the molecules have enough energy to break free but the conditions aren't right for a liquid to form.
➡️ Specific temperature and atmospheric pressure are two major factors that determine phase (i.e. solid, liquid or gas). Any substance can exist in it’s particular phase at certain range of temperature and pressure. If it’s going beyond this range then it’s convert to other phase.
➡️ Product is change it’s current phase (liquid to solid then gas) during lyophilization cycle when applying specific temperature and pressure as per following image. 

Objective of Lyophilization:

  • To extend shelf life or stability. 
  • To dry thermolabile substance or products. 
  • To reduce product weight to lower the transportation cost. 
  • To eliminate the need of refrigerator storage.

Which drug product can be lyophilized?

➡️ It is an excellent method for preserving a wide variety of heat-sensitive materials such as proteins, microbes, pharmaceuticals, tissues & plasma.

Lyophilization process at pharmaceutical industry:

➡️ In pharmaceuticals industry, lyophilization process must working as per defined cycle path.
➡️ Initially CIP, SIP, vent filter integrity, lyophilizer leak test are prerequisite to start product lyophilization activity.
➡️ After getting satisfactory results from above sequential cycles, product lyophilization activity start.
➡️ Following image is for pharmaceutical industrial operating  cycles of lyophilization to getting continuous lyophilized product with it’s original product characteristics.
The lyophilization process generally includes the following steps:
Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
Sterilizing the bulk solution by passing it through a 0.2 micron bacteria retentive filter.
Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.
Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.
Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.
Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state.
Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers.

Three main lyophilization stage.

➡️ The lyophilization process consists of three separate, unique, and interdependent processes i.e. freezing, primary drying (sublimation), and secondary drying (desorption).

1. Freezing:

➡️ Freezing can be done in a freezer, a chilled bath (shell freezer) or on a shelf in the freeze dryer. 
➡️ Cooling the material below its triple point ensures that sublimation, rather than melting, will occur. This preserves its physical form. Low temperature and low pressure are maintained. 
The rate of ice crystallization defined freezing process and efficiency of primary drying. 

2. Primary Drying (Sublimation):

➡️ It has been longest phase of lyophilization cycles, in which the pressure is lowered and heat is added to the material in order for the water to sublimate. 
➡️ Heat is introduced from shelf to the drug product by circulation of silicone oil. The vacuum speeds sublimation. 
➡️ The cold condenser provides a surface for the water vapor to adhere and solidify. The condenser also protects the vacuum pump from the water vapor. 
➡️ About 95% of the water in the material is removed in this phase. Primary drying can be a slow process. 
➡️ Too much heat can alter the structure of the material if it is not validate properly. 

3. Secondary Drying (Desorption):

➡️ During this phase, ionically-bound water molecules are removed. By raising the temperature higher than in the primary drying phase, the bonds are broken between the material and the water molecules. 
➡️ Freeze dried materials retain a porous structure. After the lyophilization process is complete, the vacuum can be broken with an inert gas i.e. Nitrogen before the material is sealed. 
➡️ Most materials can be dried to 1-5% residual moisture.

Advantages of lyophilization:

  • Ease of processing a liquid, which simplifies aseptic handling
  • Enhanced stability of a dry powder
  • Removal of water without excessive heating of the product
  • Enhanced product stability in a dry state
  • Rapid and easy dissolution of reconstituted product

Disadvantages of lyophilization:

  • Increased handling and processing time
  • Need for sterile diluent upon reconstitution
  • Cost and complexity of equipment
About the Author:
Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance. 
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer: The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.

Container Closure Integrity Test

What is container closure integrity?

Container closure integrity is the ability of a package to prevent product loss, to block microorganism ingress, and to limit entry of detrimental gases or other substances, thus ensuring that the product meets all necessary safety and quality standards. Synonymous with Package integrity.

What is container closure integrity test?

A container closure integrity test is any package leak test (either physicochemical or microbiological) that detects the presence of a package breach or gap. Some tests may also be able to identify the leak magnitude and/or location. The term container closure integrity test is synonymous with package leak test or package integrity test.

CCI testing should generally performed during three phases: 

(1) During initial development of the product packaging system
(2) Routine manufacturing
(3) Shelf life stability assessments
Development of CCI and relevance guidelines:
Container closure integrity testing methods:
➡️ It can be performed in many different ways. Broadly, container closure integrity test methods can be categorized into following two types:
1. Deterministic leak test method:
➡️ A deterministic leak test method is one in which the leakage event being detected or measured is based on phenomena that follow a predictable chain of events. In addition, the measure of leak detection is based on physicochemical technologies that are readily controlled and monitored, yielding objective quantitative data.
2. Probabilistic leak test method:
➡️ A probabilistic tests relies on a series of sequential and/or simultaneous events that are associated with large uncertainties that require large sample sizes and rigorous test condition controls.
➡️ Deterministic leak test methods are more reliable, easier to develop, validate and implement.
Differences between deterministic leak test and probabilistic leak test method:
CCIT methods:
➡️ Each test method having its different procedures, advantages and disadvantages. We have understand each and every test based on functions. 
1. Electrical conductivity test method (High voltage leak detection):
Mode: Filled container are exposed to electric current. Sparking when breach detect. 
Advantages:
  • Rapid test
  • Non destructive 
  • No sample preparation required
  • Can be used on line
Disadvantage:
  • Need conductive solution
  • Method development/validation needed for each package 
  • Package must be non porous
2. Laser-based gas headspace analysis test method:
Mode:  A near infrared diode laser light passes through the gas headspace region. The light is absorbed as a function of gas concentration and pressure. This absorption information is processed using phase-sensitive detection techniques. A microprocessor analyzes the data and yields the test results. 
Advantages:
  • Can be used for lyophilized products or oxygen-sensitive liquid products
  • Nondestructive and provides quantitative results
  • Can be used on line
Disadvantage:
  • Required a gas headspace 
  • Package must be non porous 
3. Pressure decay:
Mode: Introduces increased pressure in to the package and monitors the change (decay) in headspace pressure. 
Advantages:
  • Rigid or flexible containers
Disadvantage:
  • Only for non porous packages
4. Tracer gas detection test method:
Mode: Tracer gas e.g. Helium introduced in to the test package and spectrophotometric detection of any leaked helium. 
Advantages:
  • Rigid or flexible containers 
  • Can be used on line 
Disadvantage:
  • Liquid or solid in the leak path results in false negatives 
  • Potential to be destructive 
  • Can be slow (seconds to minutes) 
  • Package must be non-porous
5. Vacuum decay test:
Mode: Package is placed in a vacuum and the change (decay) in vacuum monitored over time. 
Advantages:
  • Rigid or flexible containers 
  • Transparent or opaque 
  • Non-destructive 
  • Porous packaging can be tested 
Disadvantage:
  • Gas headspace required at atmospheric pressure 
6. Mass extraction:
Mode: Container placed in chamber which connected to mass extraction leak test system. measurements of absolute pressure, pressure decay rate, and/or gas mass flow rate are captured. 
Advantages:
  • Rigid or flexible containers
  • Packages with a porous component can be tested with the mass extraction assay by masking the porous package component
Disadvantage:
  • Can be slow
  • Assembly time required 
7. Microbial challenge, immersion exposure test method:
Mode: Package content is replaced with microbial growth medium. The package is immersed in a suspension (air or fluid) of microorganisms. Microorganisms enter the container via any leak. Visually observed microbial growth indicates a leak.
Advantages:
  • Rigid or flexible containers 
Disadvantage:
  • Destructive 
  • Qualitative 
  • Must be non-porous & transparent containers 
  • Slow (several days or weeks) 
  • Microorganisms must be present at the leak site and access the leak freely
8. Liquid tracer test method (includes dye ingress method):
Mode:  Test package is immersed in a tracer liquid, diffusive flow of the tracer in to the container through leaks occur. The contents of the package are tested for the tracer. 
Advantages:
  • Rigid or flexible containers
Disadvantage:
  • Destructive 
  • Qualitative 
  • Must be non-porous containers 
  • Slow (minutes to hours)
9. Bubble  test method
Mode: Test package is immersed under water or coated with surfactant, maintained under pressure and bubbles visually observed. 
Advantages:
  • Rigid or flexible containers 
  • Porous packaging can be tested
Disadvantage:
  • Gas headspace required 
  • Destructive 
  • Qualitative 
  • Can be slow (seconds to hours) 
  • Trapping of bubbles can result in false negatives
10. Tracer gas (sniffer mode):
Mode: Test samples are flooded completely or partially with the tracer gas. “Soaking” a closed test sample by pressurizing with tracer gas. 
Advantages:
  • Rigid or flexible containers
  • Chosen when the leak location must be identified  
Disadvantage:
  • Destructive
  • Qualitative 
Reference: USP <1207>

About the Author:
Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance. 
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer:
The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.