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Building a Culture of Quality in the Pharmaceutical Industry

Preamble:

In the highly regulated and critical field of pharmaceuticals, ensuring the highest standards of quality is paramount.

Building a culture of quality within the pharmaceutical industry is not only a legal and regulatory requirement but also a strategic imperative for organizations to maintain their reputation, safeguard patient safety, and drive sustainable success.

This article aims to provide a comprehensive guide on how to build up a culture of quality in the pharmaceutical industry, encompassing various key aspects and best practices.

1. Leadership Commitment and Vision:

Building a culture of quality starts at the top. Leadership must demonstrate a strong commitment to quality by establishing a clear vision, values, and expectations.

This involves actively promoting quality as a core organizational principle and integrating it into the company's mission and strategic objectives. By leading by example and fostering a culture of accountability, leaders set the foundation for quality throughout the organization.

2. Regulatory Compliance:

Pharmaceutical companies must adhere to stringent regulations and guidelines to ensure the safety, efficacy, and quality of their products.

Establishing robust quality systems that comply with Good Manufacturing Practices (GMP), Good Clinical Practices (GCP), and other relevant regulatory frameworks is essential. This includes comprehensive documentation, standardized procedures, rigorous training programs, and effective quality control measures.

3. Employee Engagement and Training:

Quality culture can only thrive when employees are engaged, motivated, and equipped with the necessary knowledge and skills.

Organizations should invest in comprehensive training programs to educate employees on quality principles, regulatory requirements, and industry best practices.

By fostering a learning environment and providing ongoing professional development opportunities, companies can empower their workforce to take ownership of quality and continuously improve processes.

4. Quality Risk Management:

Effective risk management is a critical component of a quality culture. Organizations should implement robust processes to identify, assess, mitigate, and monitor risks throughout the product lifecycle.

This involves conducting risk assessments, implementing risk mitigation strategies, and establishing proactive measures to prevent quality deviations. By integrating risk management into decision-making processes, organizations can optimize resource allocation and minimize the likelihood of quality issues.

5. Continuous Improvement:

A culture of quality thrives on continuous improvement and a commitment to excellence.

Pharmaceutical companies should establish a culture of learning, innovation, and feedback. This can be achieved through regular quality reviews, performance metrics, and key performance indicators (KPIs).

Encouraging employees to identify opportunities for improvement, fostering cross-functional collaboration, and implementing corrective and preventive actions (CAPAs) are vital to drive quality enhancements.

6. Supplier Quality Management:

Maintaining high-quality standards extends beyond internal operations. Collaborating with suppliers and establishing robust supplier quality management processes is essential.

Pharmaceutical companies should implement supplier qualification programs, conduct audits, and establish quality agreements to ensure that suppliers meet the same stringent quality requirements.

Building strong partnerships with suppliers who share a commitment to quality fosters a culture of excellence throughout the supply chain.

7. Data Integrity and Technology:

In today's digital age, data integrity plays a critical role in maintaining quality standards.

Organizations must establish robust data integrity practices, including proper documentation, data security measures, and audit trails.

Implementing advanced technologies, such as electronic quality management systems (eQMS), data analytics, and automation, can enhance data integrity, streamline processes, and enable real-time quality monitoring.

Inference:

Building a culture of quality in the pharmaceutical industry is a multifaceted endeavor that requires strong leadership, regulatory compliance, employee engagement, risk management, continuous improvement, supplier quality management, and advanced technologies.

By prioritizing quality at every level of the organization, pharmaceutical companies can ensure the delivery of safe and effective products, protect patient well-being, and maintain a competitive edge in the industry.

A robust quality culture not only mitigates risks but also fosters trust among stakeholders and contributes to the overallsustainability and success of the organization.

As the pharmaceutical industry continues to evolve, regulatory requirements become more stringent, and patient expectations increase, a strong culture of quality becomes increasingly vital.

By following the key steps outlined in this article, pharmaceutical companies can establish a solid foundation for building and nurturing a quality-centric culture.

However, it is important to recognize that building a quality culture is an ongoing process that requires continuous commitment and improvement.

To sustain and further enhance the quality culture, organizations should regularly assess their performance, identify areas for improvement, and adapt to evolving regulatory and industry standards.

This includes conducting internal audits, monitoring key performance indicators, and actively seeking feedback from employees, customers, and regulatory authorities. By proactively addressing any identified gaps or issues, companies can demonstrate their commitment to continuous improvement and maintain the highest standards of quality.

Moreover, fostering a culture of quality requires effective communication and collaboration across all levels of the organization. Regular and transparent communication channels should be established to ensure that employees understand the importance of quality and their roles in upholding it.

Open dialogue, feedback mechanisms, and recognition of employees contributions to quality can further reinforce a positive quality culture and motivate employees to excel in their roles.

It is worth noting that building a culture of quality is not an isolated effort solely within the quality assurance or quality control departments. Rather, it is a collective responsibility that involves all departments and functions within the organization.

Each individual has a role to play in upholding quality standards, whether it is in research and development, manufacturing, clinical trials, regulatory affairs, or supply chain management. Therefore, cross-functional collaboration and a shared sense of accountability are crucial for success.

By nurturing a quality-centric mindset and embracing a continuous improvement philosophy, pharmaceutical companies can thrive in an ever-evolving industry while delivering safe and effective products that improve patients lives.

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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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:

Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance.

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 level	DPMO	Percent defective	Percentage 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:

Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance.

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:

Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance.

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:

Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance.

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.

Stability and Stability Zone

By Dhansukh Viradiya

⭐ Stability:

What is Stability?

➡️ Ability of a drug product to remain unchanged over time under stated or reasonably expected conditions of storage and use.

Why stability study will perform?

➡️ To establish a shelf life for the drug product and recommended storage conditions.

Selection of stability Batches:

➡️ Data from stability studies should be provided on at least three primary batches of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing.

⭐ Stability Zone:

How many stability zone?

➡️ Based on climate of world, ICH classified world in total four stability zones as per following.

➡️ The stability zones are classified based on its different temperature and humidity condition.

➡️ Stability studies of drug product depends on climate zone of different countries.

⭐ Stability testing:

What is purpose of stability testing?

➡️ It is provide document evidence on how the quality of a drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a shelf life for the drug product and recommended storage conditions.

Types of stability testing:

1. Long term testing:

➡️ Stability studies under the recommended storage condition for the re-test period or she life proposed (or approved) for labeling.

2. Intermediate testing:

➡️ Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.

3. Accelerated testing:

➡️ Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies.

Different stability zone wise countries are as per below map.

About the Author:

Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance.

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.