Showing posts with label General Topic. Show all posts
Showing posts with label General Topic. 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.

Revolution in Bacterial Endotoxin Test (BET)

Background:

Definition:

The Bacterial Endotoxins Test (BET) is a test to detect or quantify endotoxins from Gram-negative bacteria using amoebocyte lysate from the horseshoe crab (Limulus polyphemus or Tachypleus tridentatus).

Revolution in BET test from discovery to yet:

A. 1885

First recorded scientific observation of the coagulation of Limulus’ blood.

Observations upon the chemical composition and coagulation of the blood of Limulus Polyphemus and Callinectes hastatus.

B. 1953

Frederik B. Bang describes the effects of injecting a marine bacterium into Limulus polyphemus. His results indicate this causes intravascular clotting and other Gram-negative bacteria could cause similar results but Gram-positive bacteria did not produce this effect. 

This finding was the foundation which ultimately lead to the discovery of LAL many years later.

C. 1956

Renewed interest in Limulus polyphemus as a biological model for the study of disease mechanisms.

D. 1964

Discovery that endotoxin is the key factor in clotting of Limulus blood and the role of endotoxin in the extracellular coagulation of Limulus blood. 

E. 1969

James F. Cooper begins a study under the direction of Jack Levin and Henry N. Wagner to explore the use of LAL as an alternative to using the rabbit pyrogen test to detect endotoxin in pharmaceuticals.

F. 1972

LAL shown it could be applied to the detection of endotoxin in pharmaceutical drugs

G. 1973

Food and Drug Administration first proposes guidelines for the manufacture of LAL.

Food and Drug Administration proposes standards for the manufacture of LAL. 

H. 1974

Travenol Laboratories, Inc. establishes a lysate production laboratory at their Kingstree, South Carolina plant and is using their LAL to test pharmaceuticals both domestically and in some international plants.

I. 1977

FDA allows substitution of LAL for the official rabbit pyrogen test when testing biological products and medical devices providing approval is first obtained from the appropriate bureau of the FDA.

J. 1978

FDA proposal for the live release of horseshoe crabs back to their native environment after only one blood collection. 

K. 1980

The United States Pharmacopeial Convention (USP) publishes General Chapter <85> Bacterial Endotoxins Test in pharmaceutical products and medical devices.

L. 1987

The United States Food and Drug Administration publishes Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices, describing FDA’s opinion regarding the appropriate methods for validation and use of LAL for detecting the presence of endotoxin in medical products.

M. 1994

LAL methodologies advanced from gel clot and turbidimetric to the colorimetric techniques of endpoint and kinetic chromogenic in the late 1980s and early 1990s. 

N. 2001

An alternative method for endotoxin detection that used a recombinant form of Factor C (rFC) from the horseshoe crab was introduced by the National University of Singapore.

O. 2011

In July, FDA withdraws the 1987 LAL Guidance document, stating that it was obsolete and would be replaced in the future.

P. 2012

In June, FDA issues the less-prescriptive Guidance for Industry - Pyrogen and Endotoxins Testing: Questions and Answers as a replacement to the 1987 Guidance document.  

The new document states the use of recombinant Factor C methods is accepted by FDA if validated as per USP General Chapter <1225> Validation of Compendial Methods.

Q. 2016

In July, the European Pharmacopoeia publishes the revised Chapter 5.1.10, Supplement 8.8, including Recombinant Factor C (rFC) as an alternative method since, “this practice avoids the use of animal species“.

"The use of alternative reagents such as recombinant factor C as a replacement to the amoebocyte lysate eliminates the use of a reagent extracted from live animals. 

Replacement of a rabbit pyrogen test or a bacterial endotoxin test prescribed in a monograph by a test using recombinant factor C reagent or any other reagent as a replacement of the amoebocyte lysate is to be regarded as the use of an alternative method in the replacement of a pharmacopoeial test, as described in the General Notices.”

R. 2018

FDA approves first drug using the recombinant Factor C (rFC) Assay for endotoxin testing of Eli Lilly’s Emgality™ , the first drug approved by the U.S. Food and Drug Administration (FDA) to have been released using this method instead of traditional Limulus Amebocyte Lysate (LAL) based methods.

There are three techniques for this test as discuss above: 

1. Gel clot technique:

It is based on clotting of the lysate reagent in the presence of endotoxins.

The minimum concentration of endotoxin required to cause the lysate to clot under standard conditions is the labeled sensitivity of the lysate reagent.

2. Turbidimetric technique:

It is based on the development of turbidity after cleavage of an endogenous substrate.

Depending on the test principle used, this technique is further classified as either endpoint- turbidimetric or kinetic-turbidimetric. 

A.Endpoint-turbidimetric technique:

It is based on the quantitative relationship between the concentration of endotoxins and the turbidity (absorbance or transmission) of the reaction mixture at the end of an incubation period. 

B. Kinetic-turbidimetric technique:

It is a method to measure either the onset time needed to reach a predetermined absorbance of the reaction mixture or the rate of turbidity development.

3. Chromogenic technique:

It is based on the development of color after cleavage of a synthetic peptide-chromogen complex.

The chromogenic method measures the chromophore released from a suitable chromogenic peptide by the reaction of endotoxins with the LAL Reagent. 

Depending on the test principle employed, this technique is further classified as either endpoint-chromogenic or kinetic-chromogenic. 

A. Endpoint-chromogenic technique: 

It is based on the quantitative relationship between the concentration of endotoxins and the release of chromophore at the end of an incubation period. 

B. Kinetic- chromogenic technique:

It is a method to measure either the onset time needed to reach a predetermined absorbance of the reaction mixture or the rate of color development.

Alternative Endotoxin Testing Methods:

There are alternative and sustainable methods available for those pharmaceutical, medical device, and dialysis companies willing to embrace sustainable, animal-friendly innovations in endotoxin detection.

1. Recombinant Factor C (rFC) Methods derived from the Horseshoe Crab:

The National University of Singapore developed and Lonza commercialized an endotoxin test that does not require horseshoe crab blood. Instead, the DNA for one of the horseshoe crab blood clotting factors, Factor C, was cloned and is manufactured recombinantly (synthetically). Recombinant Factor C (rFC), similar to the native Factor C, is activated by endotoxin.

In the rFC test method, branded PyroGene™ by Lonza, activated rFC cleaves a fluorogenic substrate and the fluorescent signal is monitored and analyzed to quantitate endotoxin content.

The horseshoe crab provides some DNA to support this alternative advancement in endotoxin detection.

In world, horseshoe crabs are limited and/or declining, switching to the rFC method could help make a positive impact to the crab population.

The methods based on rFC have included in the European Pharmacopoeia guidelines in July 2020 as valid alternatives to the LAL test. In order to be used for product release, the rFC methods must be validated and show to provide equivalent or better performance than LAL.

2. Monocyte Activation Test:

Another method that does not require the use of horseshoe crab blood is the Monocyte Activation Test (MAT) or the In Vitro Pyrogen test.  

This test method uses human blood rather than horseshoe crab blood.  The MAT method measures the release of cytokines from blood cells due to the presence of pyrogens, such as endotoxin, in the test sample.  

The MAT is basically mimicking what occurs in our blood stream when it is exposed to pyrogenic substances.  

The MAT has an advantage over the LAL/TAL and rFC methods as it can detect non-endotoxin pyrogens. 

Monocyte activation tests (MATs) are human cell-based tests to detect and quantify pyrogens. MATs use an ELISA assay to measure cytokine release from treated blood cells.

Testing time duration of different test:

1. Rabbit Pyrogen Test:

 It is performed in 3 hours (after pre-test preparation)

2. LAL and rFC Test:

It is performed in about 2 hours

3. Monocyte Activation Test (MAT):

It is performed in 24 hours

Is Validation a factor in choosing what test to perform?

1. Rabbit pyrogen test – nominal

2. Bacterial endotoxin test - product-specific, regulatory approval

3. rFactor C test - product-specific, regulatory approval

4. Monocyte Activation Test - product-specific, regulatory approval

Reference:

1.https://www.horseshoecrab.org/med/timeline.html

2. USP <85> Bacterial Endotoxins Test in pharmaceutical products and medical devices.

3. USP <151> Pyrogen Test.

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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What’s New in EU GMP Annex 1 “Manufacture of Sterile Medicinal Products”?


The newest version of Annex 1 that was proposed in December 2017 and updated in 2020 is an entirely rebuilt guidance document which were revised in 2003 and 2007. Updated revised guideline has been published in August 2022.


Some points are key points in revised Annex 1. Which we need to focus on current regulatory requirements and need to re-evaluate our current practice with compliance of expectation of regulatory.


The deadline for coming into operation of Annex 1 is 25 August 2023, except for point 8.123 which is postponed until 25 August 2024.

 


Section 1: Non-Sterile Products incorporated in Scope


“The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates but where the control and reduction of microbial, particulate and pyrogen contamination is considered important.”


Section 2: Introduction of a Contamination Control Strategy


“A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks associated with contamination. The CCS should be actively updated and should drive continuous improvement of the manufacturing and control methods.” 


Section 3: Introduction of a Pharmaceutical Quality System


“The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that microbial, particulate and pyrogen contamination is minimized in sterile products.” 


Section 4:

RABS as Part of the CCS


“Restricted Access Barrier Systems (RABS) and isolators are beneficial in assuring the required conditions and minimizing the microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.” 


Detailed Airlock Measures


“Airlocks should be designed and used to provide physical separation and to minimize microbial and particulate contamination of the different areas, and should be present for material and personnel moving between different grades. Wherever possible, airlocks used for personnel movement should be separated from those used for material movement. Where this is not practical, time-based separation of movement (personnel / material) by procedure should be considered. Airlocks should be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock should, in the “at rest” state, be of the same cleanliness grade (viable and non viable) as the cleanroom into which it leads. 

The use of separate changing rooms for entering and leaving Grade B cleanrooms is desirable. Where this is not practical, time-based separation of activities (ingress/egress) by procedure should be considered. Where the CCS indicates that the risk of cross-contamination is high, separate changing rooms for entering and leaving production areas should be considered.”

 

Section 5: Equipment monitoring


“Equipment monitoring requirements should be defined in “user requirements specifications” during early stages of development, and confirmed during qualification. Process and equipment alarm events should be acknowledged and evaluated for trends. The frequency at which alarms are assessed should be based on their criticality (with critical alarms reviewed immediately).”


Section 6: Monitoring Systems for WFI


“WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, (unless justified otherwise) as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk and the outcome of qualification.” 


Section 7: Personnel Requirements


“The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified, trained and experienced in the manufacture and testing of sterile products, and any of the specific manufacturing technologies used in the site’s manufacturing operations, to ensure compliance with GMP applicable to the manufacture and handling of sterile products.” 


Section 8:

PUPSIT Requirements


“The integrity of the sterilized filter assembly should be verified by integrity testing before use, to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade filter that is used to sterilize a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. Test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold test. It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be possible after sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of non-sterility.” 


New Section for Closed Systems


“It is critical to ensure the sterility of all product contact surfaces of closed systems used for aseptic processing. The design and selection of any closed system used for aseptic processing should ensure maintenance of sterility. Connection of sterile equipment (e.g. tubing / pipework) to the sterilized product pathway after the final sterilizing filter should be designed to be connected aseptically (e.g. by intrinsic aseptic connectors or fusion systems).” 


New Section for Single Use Systems


“SUS should be designed to maintain integrity throughout processing under the intended operational conditions. Attention to the structural integrity of the single use components is necessary where these may be exposed to more extreme conditions (e.g. freezing and thawing processes) either during routine processing or transportation. This should include verification that intrinsic aseptic connections (both heat sealed and mechanically sealed) remain integral under these conditions.” 


Reference:


1.       Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 1 “Manufacturing of Sterile Medicinal Products” revised on August 2022.

2.      Regulatory site link: https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en


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.

Key factors affecting on product Sterility Assurance

Preamble:

Definition:

“Sterility assurance is a level of confidence that a particular product or unit that is purported to be sterile is sterile.”

➡️Sterility assurance is achieved through multiple practices and procedures. A different variables of contamination control that help to increase confidence in sterility assurance and sterile products.

➡️USP <1211> is a general information chapter on sterility assurance. The chapter states that “an item is deemed sterile only when it contains no viable microorganisms. Sterility testing described in USP <71> Sterility Tests.

➡️The test only indicates that the subset of articles from a lot that are tested are sterile. The test is destructive in that every unit that is tested is either consumed or no longer sterile after the test is performed. To help ensure consumer safety, additional measures must be put into place to add assurance that the entire batch or lot of products manufactured is sterile.

➡️Figure 1 shows several factors that influence sterility assurance. The factors listed in Figure 1 should be considered for their impact on the sterility of the final product.

Figure 1: Key elements to influence on Sterility Assurance
 


➡️ A sterility assurance program should be fit for purpose for the product or device that is being manufactured. A holistic sterility assurance program for an aseptic manufactured product could include the following components.

1.      Personnel

1.1.Training

➡️ Personnel must be properly trained, educated, and/or supervised to be involved with aseptic processing. The training records must be maintained.

➡️Training concepts should include the importance of proper aseptic technique and clean room behaviours. It must be recognised that humans are the primary source of contamination in the clean room environment.

➡️Retraining and qualification of personnel should be done on a routine basis to keep personnel sensitised to the importance of aseptic technique.

1.2.Personal Hygiene and Sanitation Practices

➡️It must be procedures and training that govern personnel hygiene, sanitation, aseptic technique, aseptic behaviour in the clean rooms and aseptic gowning practices.

➡️Personnel must adhere to sanitation and health precautions designed to avoid contamination of the test, environment, and/or product. Personnel must also adhere to gowning and personal protective equipment procedures. If an employee is feeling ill, they must inform their supervisor of any health or medical condition that may have an adverse effect on a test, product, or environment.

➡️Personnel must also be monitored for microbial growth and undergo gowning qualification training to ensure aseptic status of the manufacturing or testing environment.

➡️To protect exposed sterilized product, personnel should to maintain gown quality and strictly adhere to appropriate aseptic techniques.

1.3.Personnel Flow

➡️It must be procedures and practices regarding personnel flow. Personnel must follow established entry and exit routes to prevent cross contamination.

➡️The routes should include different levels of gowning for each grade of the clean room environment. These routes must also be established in standard operating procedures (SOPs) and understood by personnel.

2.      Procedural Control

2.1  Cleaning Process

➡️The well-defined cleaning process in place to assure contamination level is not go beyond the approved specification limit and subsequent not cross contaminated to next product.

➡️Cleaning process should be validated by using worst case molecules and routine monitoring to be done whenever changeover between two products to get assurance that validated cleaning procedure are in well placed.

2.2  Line clearance procedures

➡️A well-established line clearance procedure should be placed which ensured that the area and equipment are required during manufacturing and filling activities of drug products are free from any potential cross contamination/mix-ups.

➡️There are well elaborated checkpoint are available in line clearance of  critical stages of process.

➡️Personnel involved for line clearance should be trained on SOP.

2.3  Manufacturing Practices

➡️The manufacturing process i.e. all interventions and aseptic connections must be monitored and controlled. Proper aseptic technique and personnel behaviours must be utilized to prevent cross contamination of product during manufacturing.

2.4  Decontamination

➡️Decontamination practices for aseptic processing must be documented in SOPs. This could include chemically sanitizing equipment to take into the clean rooms, wiping items down with disinfectants, or using decontamination devices such as vaporized hydrogen peroxide (VHP) generators or autoclaves.

2.5 Sterilization and Depyrogenation

➡️The use and sterilization of equipment, components, or other materials for aseptic processing must be governed in SOPs. This could include purchasing items that are ready to use or preparing the items for use in-house.

2.6  Validation

➡️Media fills (Aseptic process simulation) help to demonstrate that the manufacturing process can produce a sterile final product. The manufacturing process should include inherent interventions & corrective interventions and aseptic connections.

➡️Media fill study will show contamination control effectiveness throughout the manufacturing process.

➡️Process validation proves that process is capable of consistently delivering sterile quality product.

3.      Material

3.1  Product and Material Movement

➡️It must be procedures and practices for product and material flow to prevent cross contamination.

➡️The routes should include levels or methods of sanitization of products, materials, and/or waste as they enter or exit the clean room areas. These routes must also be established in standard operating procedures and understood by personnel.

3.2  Supplier Qualifications

➡️Qualifying suppliers is an important approach to control items that are purchased sterile and ready to use. It is important that vendors are trusted to provide quality supplies to maintain sterility assurance of the final product that is being manufactured. Supplier qualifications must be governed by SOPs.

3.3  Material Control

➡️Products and materials must also be controlled to prevent contamination and increase sterility assurance. Raw materials, components, active pharmaceutical ingredients, container closures, and product contact surfaces should all be monitored and controlled.

➡️Sterility must be assured for cleaning solutions, tools and equipment, raw materials, container closures, and any other materials that will be introduced into the clean room area.

3.4  Storage Conditions

➡️When considering storage conditions, it is important for warehouse cleanliness, order, and quarantine areas when  all raw material, container closure material are stored. Temperature and humidity should be monitored and controlled when required.

➡️Conditions should be maintained to ensure the sterility of the final product. In addition, container closure integrity should be established to ensure the product remains sterile in its packaging.

4.      Machine/Equipment

➡️The use and preparation of equipment for aseptic processing must be documented in SOPs and respective batch records.

➡️It must be designed appropriately for the intended use and housed in a manner to prevent cross contamination. Equipment used in the generation, measurement, or assessment of data and equipment used for facility environmental control must be of the specified design and capacity to function according to GMPs.

➡️The equipment must be suitably located for operation, inspection, cleaning, and maintenance. It must be inspected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data must be tested, calibrated, standardized, and/or sterilized.

➡️The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.

➡️Equipment should be appropriately designed to facilitate ease of sterilization. It is also important to ensure ease of installation to facilitate aseptic setup.

➡️Horizontal surfaces or ledges of equipment that accumulate particles should be avoided. Equipment design should not obstruct unidirectional airflow in critical areas.

4.1  Equipment Qualifications

➡️Equipment designed such as for it intended use will be demonstrated by successful qualification.

➡️Equipment should also be qualified for use in the clean rooms. There should be cleaning validations that include clean and dirty hold times of equipment.

4.2  Maintenance

➡️Annual maintenance planner of all equipment to be prepared and maintenance must be performed within predefined duration.

5.      Facility Management

5.1  Design

➡️The design of the facility should be documented on approved layouts and flow diagrams to help personnel in their daily tasks.

➡️The facility must be constructed to prevent microbial contamination. This could include items like differential pressure cascades, the use of classified areas, and temperature monitoring.

➡️Separate areas should be available for the storage and quarantine of materials. The warehouse must be neat, clean, and temperature/humidity controls where appropriate. Cardboard or other items containing cellulose fiber should not be allowed in clean areas as they could be a source of mold contamination. 

➡️Laboratory practices must also be implemented to prevent microbial contamination from outside of clean rooms. This could include changing uniforms and shoes and using proper aseptic gowning practices wherever applicable.

5.2  Supporting Clean areas

➡️The effects from supporting areas should also be considered. If an adjoining room has microbial contamination, that contamination could migrate into the inner core of the clean rooms. Transition areas should be monitored and controlled.

➡️This areas should be designed such as to minimize the level of particle contamination in final product and control the microbiological content (bio burden) of articles and components that are subsequently sterilized.

5.3  Decontamination, Cleaning, and Disinfection Programs

➡️Decontamination, cleaning, and disinfection programs must be established. The programs must be governed by SOPs and should describe what gets cleaned, how the cleaning is performed, how often the cleaning is performed, what cleaning agents are utilized, and the validation of the cleaning, decontamination, or disinfection process.

➡️Room cleanings should include items like the walls, floors, ceilings, and equipment. Also, there should be established clean and dirty hold times for equipment and the clean rooms.

➡️When utilizing disinfectants, consider items like disinfectant efficacy date, wet contact times, and the method of application of the disinfectants. Cleaning, disinfection, and/or decontamination concepts should be considered for both product contact and non-product contact surfaces.

6.      Measurements

6.1  Laboratory Testing & control

➡️Laboratory testing are sterility testing, endotoxin testing, bioburden testing, raw material testing, in-process testing, finished product testing, and container closure integrity testing.

➡️A sterile product is to undergo analysis for microbial endotoxins and sterility testing to assure the absence of contamination. 

➡️Laboratory practices must also be implemented to prevent microbial contamination from outside of clean rooms. This could include changing uniforms and shoes and using proper aseptic gowning practices wherever applicable.

7.    Environmental Monitoring Program

➡️Temperature, %RH and differential air pressure should be maintained through qualified installed AHU system.

➡️Environmental monitoring assesses the microbial contamination level in the cleanrooms and adjacent areas. This data may highlight areas that need extra cleaning, monitoring, and/or maintenance.

➡️Air (i.e. Viable and Non-viable airborne particulates) and surfaces are routinely monitored within the clean rooms to make sure the environment continuously meets specifications.

➡️Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination occurs.

➡️The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures.

➡️It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production.

➡️Clean areas must be validated and maintained. This should include environmental monitoring qualification programs (EMPQ) and clean room qualifications.

➡️High efficiency particulate air (HEPA) and heating, ventilation, and air conditioning (HVAC) systems should be used with differential pressure cascades, temperature controls, and humidity controls to prevent microbial contamination.

➡️If the temperature is too hot or humid, people could sweat, compromising their clean room gowning. In addition, when pressure cascades are not controlled properly, microbes could enter the clean rooms. Excessively humid environments can increase the potential for fungal contamination.

Reference:

➡️FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. US Department of Health and Human Services. 2004.

➡️EMA Annex 1 – Manufacture of Sterile Products.

➡️United States Pharmacopeia (USP) <1211> Sterilization and sterility assurance of compendial articles.

➡️United States Pharmacopoeia Chapter <71> Sterility tests.

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.