Showing posts with label Current affairs. Show all posts

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:

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.

Buy most selling mobiles at Amazon through following link address

Realme Narzo N53

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:

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.

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.

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:

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.

Challenges for current pharmaceutical companies

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

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

1. Required qualified workforce

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

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

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

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

2. Data collection and statistical evaluation

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

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

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

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

3. Supply chain disturbance

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

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

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

4. Difficulties to manage brand against rising consumer expectation

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

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

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

You may also like:

1.USFDA inspection & it's different types

2.Different forms for USFDA inspection- Form 482/483/484
3.Establishment Investigation Report (EIR) of FDA- NAI/VAI/OAI
4. Stability and Stability Zone
5. Cleaning Validation
6. Drug product recalls
7. FDA Acronyms & it's meaning
8.Quality risk management for introduction of new product
9. Container closure integrity test
10.Lyophilization or Freeze Drying
11. Six Sigma

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.

How to Reduce Repeated Deviations or Incidents

Every deviation is meaningful to improve your existing process, practice and system in some extent.

➡️ If any deviation is repeated a significant number of times, it could turn into a major deviation and must be treated as such. The investigation of the deviation should also determine the reason why the implemented corrective actions were not successful.

➡️ Your repeated deviation revealed that your manufactured product, process and environment where you manufacture should become risky and all come under question mark??? Some times, companies was not affording repeated deviations, and soon will be getting regulatory action.

➡️ If you want to save your company from repeated deviation and regulatory actions, you should adopt following easy steps.

1. Change your Attitude:

➡️ Whenever any deviation generates, don’t blame inter or intra department personnel, machine, process, system, etc. Because every deviation is a pill to cure your deficiency about existing systems, process and practice, etc. It will act as to rebuild your process, practice and system by implementing effective proper CAPA.

➡️ So, if you want to reduce deviations then you must be working together and don’t balm each other and investigate in a proper way with the conclusion of assignable or probable root cause and its other impacted factors.

➡️ Reported deviation immediately after generation without fail and close within timeline based on criticality. Now onwards change your attitude when any new or repeated deviation observed.

2. Focus on multiple contributing factors instead of root cause:

➡️ Mainly generation of repeated deviation is only happening due to prioritize single root cause.

➡️ If you want to prevent the incident happening again, you must need to remove as many of the contributing factors as possible, not just single root cause.

➡️ There is number of contributing factors in queue before the deviation happens. So, start digging and don’t stop at the first and most visible contributing factor.

➡️ Focus on those contributing factors which have the critical impact, not on those factors which have easiest to solve.

➡️ Hence, remove the term ‘root cause’ from your procedure and mindset.

3. Know your process and product:

➡️ You can’t be investigating of deviation without an understanding of your product and process in deeply.

➡️ Problem solving is dependent to your knowledge about products and process. You must know your product key critical process parameters, critical quality attributes, product quality, safety and efficacy parameters.

➡️ If you don’t know your product and process then inadequate CAPA will be initiated based on investigation of deviation. Which will be recurring repeated deviation over the time.

4. Don’t treat every deviation in the same way:

➡️ If you treat every deviation the same, you are likely to suffer from deviation blindness, which are familiar symptoms too many peoples now a days.

➡️ If you don’t segregate deviation based on its risk. It will become dangerous to your product as well as process.

➡️ Whenever any deviation log, you must need to prioritize the risk and take your time to investigate based on criticality.

➡️ Don’t be follow the traditional techniques that you have to close every deviation within the timeline like 30 days.

5. Go to the scene instead of Desks:

➡️ If you want to fix deviation properly, you must go to the place at where deviation occur as soon as possible.

➡️ As discuss earlier that every deviation is not the same. Hence, stand up your convenient place and go to the scene where problem arise. Otherwise generating CAPAs are same or usually based on assumptions with past experience of the same type of deviation.

6. Don’t encourage people to reduce deviation numbers are good:

➡️ We all know that we need accurate performance measures to make the right decision.

➡️ What most people don't know is there before selecting any performance measure, you must first decide on what behaviors you wish to increase then select the most appropriate measure.

➡️ When encouraged to reduce deviations, people usually enforce and deviation appeared to decrease in number an overnight. Such a measure may encourage number reporting of deviation, particularly if blame culture is alive and kicking. You need to change your attitude.

➡️ Deviation are good news not a bad one. It provides you that learn from the experience.

Summary:

When investigating deviations, please make sure you don’t focus on finding only root cause. Look into relevant contributing factors and take an appropriate CAPA. Never treat every incident the same. If your policy allows 30 days to ‘close out’ of all critical and minor investigations then it’s too dangerous to your firm. You have to create a culture where people report the incident on time and you clearly do understand their importance. If you routinely complete investigations from behind a desk one thing is guaranteed that your diagnosis of the problem and prescribe for those CAPAs are probably wrong. Ask yourself that have you expert and knowledge of your product and process before starting of investigation.

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.