Sunday 31 March 2013

Microbial identification

Dennis Champagne, Director, Laboratory Services, at Microtest Laboratories, Inc., has written an article on microbial identification for Controlled Environments, which can be viewed on-line.

The article is interesting in that it looks at modern and rapid methods for microbial identification, including genotypic methods. As the article indicates:

“The new microbial identification systems, such as the MicroSEQ® instrument from Applied Biosystems, employ ribosomal DNA (rDNA) sequencing to replace phenotypic microbial ID methods, fatty acid ID methods, traditional plate identification, ELISA, or antibody-based methods. Using a phylogenetic approach, the systems sequence the stable 16S ribosomal RNA (rRNA) gene present in all bacteria. For fungi, they sequence the D2 region of the large fungi sub-unit. (Note that a single isolated colony—alive or dead—is sufficient for identification purposes.) After sequencing the rRNA gene, the systems automatically compare the results to validated sequences in their customizable microbial libraries. They then deliver a list of the closest matches, ranked according to genetic distance from the sample.”

To view the article, go to Controlled Environments.

Posted by Tim Sandle

Saturday 30 March 2013

Fungal spore detection

A new method has been developed for measuring levels of indoor fungal spores. The scientists describe a new method, which involves collecting air samples on a piece of commercially available aluminum foil, and then analyzing the spores with a technique called Raman microspectroscopy (RMS). They used the method to detect and identify single spores from seven common types of mold. The team says that use of the new test could help with many problems in the public health, forensics sciences and environmental fields.

The object was to develop a fast and easy method that can reliably detect and identify low levels of airborne mold – even single spores. The findings have been published in ACS’ journal Environmental Science & Technology.

The paper is by Sutapa Ghosal et al and is titled “Raman Microspectroscopy-Based Identification of Individual Fungal Spores as Potential Indicators of Indoor Contamination and Moisture-Related Building Damage”.

Posted by Tim Sandle

Implementing a disinfectant for Pharmaceuticals and Healthcare

How to successfully implement a disinfectant into the Pharmaceutical, Healthcare, Cosmetics & NHS Industries
One-day Seminar Thursday 20th June (Venue TBC)
FREE to Pharmig Members (small fee for non-members)

In response to popular demand, Pharmig are delighted to offer a disinfectant seminar which will be held on Thursday 20th June 2013. Pharmig would like to offer a complimentary place to one Pharmig member from each site to thank members for their continuing support (non-members £150-00). Places are strictly limited and are offered on a first come-first served basis. Please contact Pharmig for further details.

Objective of this seminar
The seminar aims to outline the process for selecting the most effective product for your facility by generating a compliant and comprehensive validation package. Once selected and validated, guidance will be given on how to transfer into routine use.

The CDC Handbook: A Guide to Cleaning and Disinfecting Cleanrooms

Topics covered include:
·       Regulatory aspects
·       Selection
·       Validation
·       Application techniques
·       Implementing a new disinfectant
·       What can go wrong: key risks for contamination control

For details go to the booking form or contact Pharmig.

Posted by Tim Sandle

Friday 29 March 2013

On-line calibration reference book

The company Vaisala are offering a free on-line ebook in relation to the calibration of equipment.

The introduction to the book explains its purpose:

“This book was written to help the readers with the measurements they perform. The intent is to help the readers and their organizations determine the most appropriate activities that ensure the quality of their measurements. We hope this book provides the readers with a framework in which to place their own activities.

This book serves as a generic introduction to calibration. We discuss the rationale behind calibration, and the factors that affect the need to calibrate. The book also provides some specific information on calibration of relative humidity, dewpoint temperature, temperature, and barometric pressure.”

To access the book, go to Vaisala

Posted by Tim Sandle

Thursday 28 March 2013

Monitoring for psychrophilic bacteria in cleanrooms

Tim Sandle and Kerry Skinner have undertaken research into the presence of psychrophilic and psychrotolerant microorganisms in pharmaceutical facility cold rooms. The study has been published in the Journal of Applied Microbiology.

Here is a summary of the study:

Aims: To examine for psychrophilic or psychrotolerant micro-organisms in pharmaceutical cold rooms (in relation to numbers, incidents and species) and to determine, where such micro-organisms are present, whether standard microbiological environmental monitoring regimes require modification. This is presented as a case study.

Methods and results: Comparative environmental monitoring within different pharmaceutical facility cold rooms (using standard mesophilic and low temperature incubation). Data were collected over two periods, 5 years apart. The results indicated that psychrophilic micro-organisms were not present and that those micro-organisms deemed psychrotolerant, primarily pseudomonads, could be grown on standard media under mesophilic conditions.

Conclusions: Psychrophilic micro-organisms were not detected and those considered to be psychrotolerant were only found in low numbers. Pyschrotolerant organisms were recovered under both low temperature incubation conditions and under standard conditions (between 20 and 35°C). Further evaluation may be required, using alternative agar, and microbiologists should regularly review the species recovered to note differences between different environments.

Sandle, T. and Skinner, K. (2013). Study of psychrophilic and psychrotolerant microorganisms isolated in cold rooms used for pharmaceutical processing, Journal of Applied Microbiology, 114 (4), 1166—1174

Posted by Tim Sandle

Wednesday 27 March 2013

USP 1116 and cleanroom environmental monitoring

Tim Sandle has written an article reviewing the changes to the USP chapter relating to the environmental monitoring of areas used for the manufacture of sterile products (chapter 1116, which was issued in the 35th edition of the USP).  The analysis is from a European perspective.

The main changes with the USP were:

To focus the chapter on environmental monitoring only, by removing information relating to aseptic process validation and to the physical aspects of cleanroom operations.

To focus the document exclusively on the monitoring of aseptic environments, by removing references to the monitoring of non-sterile environments.

To reconsider the alert and action level (limit) concept.

The article has been published in the latest edition of the GMPReview. The reference is:

Sandle, T. (2013). New guidance for environmental monitoring in cleanrooms, GMP Review, Vol. 11, No.4, pp9-11.

Posted by Tim Sandle

Tuesday 26 March 2013

Sterilization by Gamma Radiation for Single-Use Disposable Technologies

Pharmaceutical Technology are hosting a free to read paper by Tim Sandle and Madhu Raju Saghee entitled "Application of Sterilization by Gamma Radiation for Single-Use Disposable Technologies in the Biopharmaceutical Sector".

The introduction to the article reads:

"The primary method for the sterilization of single-use technology is by gamma irradiation. This is because plastics cannot be subjected to heat-based methods of sterilization without damaging the mould (i.e., styrene and other plastics are temperature sensitive). Other alternative methods, such as gaseous sterilization by ethylene oxide, that although used on occasions, can leave unwanted and potentially toxic residuals (e.g., ethylene glycol and ethylene chlorhydrin) post-sterilization (4). Other alternative sterilization methods (e.g., liquid peracetic acid immersion system and plasma sterilization processes) are not sufficiently well established (5). Electronic beam irradiation is an alternative method of radiation to gamma. This is a concentrated, highly-charged stream of electrons generated by the accelera tion and conversion of electricity (6). Electronic beam radiation is not commonly used for single-use disposable systems due to its relatively limited ability to penetrate some types of plastics. Therefore, single-use systems are typically sterilized using gamma rays (i.e., electromagnetic wave radiation). Despite the widespread application of the gamma irradiation, the process remains the only primary sterilization method not described in either the European Pharmacopoeia or United States Pharmacopeia (USP).

This paper outlines the process of gamma radiation and describes the important aspects of validation. The paper is designed to provide a guide to those wishing to understand more about the process and to offer advice for quality assurance personnel who are required to audit the sterility assurance of gamma radiation." 

To read the full paper, go to Pharmaceutical Technology.

Sandle and Saghee are the editors of the new book "Cleanroom Management in Pharmaceuticals and Healthcare".

Posted by Tim Sandle

Monday 25 March 2013

Validation and Operation of a Sterility Testing Isolator

A new peer-reviewed article of interest has been published 'Validation and Operation of a Sterility Testing Isolator: a Study Proposal'.

The article has been written by Tim Sandle and Nancy Tours for the re-vamped Institute of Validation Technology website's on-line Journal of Validation Technology.

The opening section of the article reads:

"One of the concerns with the sterility test, especially when high-value products are handled, is the risk of false positives that can lead to expensive and lengthy failure investigations (and where proving a false positive is extremely difficult, therefore, the outcome can often be batch rejection). A false positive can be described as a contaminating microorganism that has been transferred into the test media through cross-contamination by personnel or from the test environment; in contrast, to microbial contamination being present in the product under test.  Where the sterility test is..."

The reference is:

Sandle, T. and Tours, N. (2013).  Validation and Operation of a Sterility Testing Isolator: a Study Proposal, Journal of Validation Technology, Vol. 19, No.1, on-line.

To find out more about the article and how to view it, go IVT

Posted by Tim Sandle

Sunday 24 March 2013

Determining The Right Glovebox For Accurate Level Of Containment

A Glovebox is a sealed enclosure that allows materials handling through long, relatively impermeable gloves secured to ports in the walls of the enclosure. The purpose is protection or isolation, which is provided by the physical barrier. Depending on the type of system, the physical barrier may be to isolate a sensitive material inside the box from environmental contamination (controlled atmosphere type) or to protect the operator from hazardous materials being manipulated inside the box (ventilated type). Most systems have a main chamber where manipulations occur and a smaller transfer or antechamber where samples, small apparatus, and supplies are introduced into the main chamber.

This is the introduction to an article by Gary Roepke and Bob Applequist, published on Pharmaceutical Online. Readers may find the article of interest.

Posted by Tim Sandle

Saturday 23 March 2013

PHSS Storage of Blood Products – Temperature Monitoring and Mapping Guide

The UK science society, the PHSS, have published a free guide titled ‘Storage of Blood Products – Temperature Monitoring and Mapping Guide’.

The scope of the guide reads: “This document provides guidelines for the temperature monitoring and mapping requirements for the storage and distribution of blood components, products, reagents and test kits in blood establishments and hospital blood banks and gives some examples of what to do in the event of a temperature excursion outside of specification.”

The document does not refer to plasma products. 

To access go to: PHSS

Posted by Tim Sandle

Friday 22 March 2013

PDA Technical Report No. 61 (TR 61): Steam In Place

News from the PDA: PDA Technical Report No. 61 (TR 61): Steam In Place has been released.

"The primary objective of the task force responsible for this technical report was to develop a scientific technical report on Steam In Place (SIP) processes that provides recommendations for use by industry and regulators. This document focuses on the various applications of steam for in situ sterilization for "sterile" applications and for in situ sanitization and other bioburden control applications widely used for systems that do not claim to be "sterilized" via steam. Risk management employed throughout the lifecycle of SIP equipment and processes to efficiently focus and allocate resources commensurate with the probability of impacting final product purity and safety is also covered.

The task force was composed of European, North American, and South American industry professionals to ensure the methods, terminology, and practices of SIP reflect sound science and can be applied globally."

For details, see the PDA.

Posted by Tim Sandle

Cleanroom Cleaning and Disinfection: Eight Steps for Success

The correct use of detergents and disinfectants is important for contamination control. In view of this, Tim Sandle has written an article for Controlled Environments magazine.

“The object of cleaning and disinfection is to achieve appropriate microbiological cleanliness levels for the class of cleanroom for an appropriate period of time. Thus the cleaning and disinfection of cleanrooms is an important part of contamination control. This article examines the eight key steps to be followed, in relation to cleaning and disinfection, in helping to keep cleanrooms 'clean'.”

To read the full article on-line, go to Controlled Environments

Posted by Tim Sandle

Thursday 21 March 2013

Food safety and microbiology

There is an interesting interview with Mike Peck from the Institute of Food Research in Laboratory News. In the interview Mike Peck discusses food safety and touches upon microbiological aspects.

Here is an extract:

“The Institute of Food Research (IFR) has an outstanding record in delivery of research outputs that support national and international industry and regulation. Research at IFR on microbiological food safety is focused on understanding how three major foodborne bacterial pathogens of the greatest concern to the UK (Salmonella, Campylobacter and Clostridium botulinum) survive and grow in the food chain. Salmonella and Campylobacter are both enteric zoonotic pathogens that cause infection, and are a major cause of morbidity and mortality worldwide. C. botulinum is a highly dangerous spore-forming bacterium that is responsible for botulism, a severe and deadly disease.

In part due to its ability to thrive and quickly adapt to the different environments in which it can grow, Salmonella remains a serious cause of food poisoning in the UK and throughout the EU. New research involving a team of IFR scientists has taken the first detailed look at the molecular mechanisms employed by Salmonella that enables their survival and growth in the food chain. Importantly we have determined how Salmonella adapts when it enters a new environment, which could provide clues to finding new ways of reducing transmission through the food chain, and thus preventing human illness.

Bacteria can multiply rapidly, potentially doubling every 20 minutes in ideal conditions. However, this exponential growth phase is preceded by a period known as lag phase, where no increase in cell number is seen. Lag phase was first described in the 19th Century, and was assumed to be needed by bacteria to prepare to exploit new environmental conditions. Beyond this, surprisingly little was known about lag phase, other than that bacteria are metabolically active in this period. But exactly what are bacteria doing physiologically during this period?”

To read the full article, go to Laboratory News.

Posted by Tim Sandle

Wednesday 20 March 2013

Cleanrooms: construction and technology

Tim Sandle and Madhu Raju Saghee, editors of 'Cleanroom Management in Pharmaceuticals and Healthcare', have written the first of a two part article surveying the latest innovations in cleanroom technology and design. The article is published in the May 2012 edition of Pharmaceutical Manufacturing and Packaging Sourcer (PMPS).

The article addresses cleanrooms and clean air devices.

Here is an extract:

“In recent years there have been considerable advancements with cleanroom design. These are aimed at ensuring that the cleanroom is designed in a way which ensures that it meets the requirements of the user and is designed in the optimal way to ensure contamination control. It is important to dedicate time to designing cleanrooms and the equipment located in cleanrooms for, if there is a design fault in one part, this will affect the items of equipment and if there is a fault in conception stage this will be expensive and time consuming to rectify.

For cleanroom design, modern approaches utilise Computer Aided Engineering software for the design process, such as Building Information Modelling (BIM) software. BIM covers geometry, spatial relationships, light analysis, geographic information, quantities and properties of building components (for example manufacturers’ details). BIM can be used to demonstrate the entire building life cycle, including the processes of construction and facility operation. Quantities and shared properties of materials can be extracted easily. Systems, assemblies and sequences can be shown in a relative scale with the entire facility or group of facilities.”

The second part of the article will be published in the following issue.

The reference is:

Sandle, T. and Saghee, M.R. (2012). ‘Setting The Scene’, Pharmaceutical Manufacturing and Packaging Sourcer, May 2012, pp38-43

The article is an introduction to some of the topics covered in a forthcoming book on cleanrooms. The book is called “Cleanroom Management in the Pharmaceutical and Healthcare sectors”, edited by Tim Sandle and Madhu Raju Saghee, and will be published by Euromed later this year.

See PMPS for further details and an extract: PMPS

Posted by Tim Sandle

Tuesday 19 March 2013

Quality Management System

Tim Sandle has written a short paper on the key elements of Quality Management Systems, The paper has been published on the A3P website.

Here is an extract:

“The basis of a Quality Management System is set out in: ISO/FDIS 9001:2000 - Quality management systems – Requirements. The adoption of a QMS needs to be a strategic decision of an organisation, and is influenced by varying needs, objectives, the products/services provided, the processes employed and the size and structure of the organisation. A QMS must ensure that the products/services conform to customer needs and expectations, and the objectives of the organisation.”

To view the article, go to: A3P

Sandle, T. (2012). “Quality Management System”, A3P website, published 1st May 2012 

Posted by Tim Sandle

Monday 18 March 2013

Compounded Products Recall: Potential Mold Contamination

A special report by Tim Sandle.

A New Jersey compounding pharmacy has temporarily shut down its operations after Connecticut hospital officials reported finding visible mold in bags of an injection drug.

The U.S. Food and Drug Administration (FDA) has announced that Med Prep Consulting, Inc.  is recalling all lots of all products compounded at its facility, due to lack of sterility assurance (see the end of this article for a list of the products being recalled). The move followed a voluntary consent order enacted Friday that will remain in effect until at least March 22.

The level of recall is to the user: regional hospital pharmacies and related departments, and physician’s office practices. The recall resulted from the pharmacy being notified by a Connecticut hospital that it observed visible particulate contaminants in 50 ml bags of MAGNESIUM SULFATE 2GM IN DEXTROSE 5% IN WATER, 50ML FOR INJECTION intravenous solution, confirmed to be mold

These were unique and distinct lots compounded and dispensed by the pharmacy to the Connecticut hospital. At this time a total of five (5) contaminated bags were discovered. The affected products are used for a wide range of therapeutic uses for hospitalized inpatients and outpatients, and, patients directly treated by a health care professional at a physician’s office practice facility or clinic. All products are packaged in plastic infusion bags, plastic infusion devices, plastic syringes and glass vials.

To date, no injuries or illnesses have been reported. According to NBC News, New Jersey Health Commissioner Mary E. O'Dowd said in response to the incident: "This investigation is evolving. At this time, in an abundance of caution, the Department of Health recommends that any health care facility that has received products from Med Prep should inventory them and remove them from use."

Med Prep is a specialty intravenous I.V. pharmacy licensed by the State of New Jersey offering sterile compounding services. In operation since 1994. There was no word of the recall via a search of the company web site.

This incident follows on from the fungal contamination found in three lots of medication used for epidural steroid injections, which was packaged and marketed by the New England Compounding Center (NECC), a compounding pharmacy in Framingham, Massachusetts.

Compounding pharmacies are authorized, in the U.S., to combine, mix or alter ingredients to create specific formulations of drugs to meet the specific needs of individual patients, and only in response to individual prescriptions.

There is debate among governments and regulators about which agency has primary oversight of compounding pharmacy. The FDA says it has less power to overseas compounding pharmacies than it does traditional manufacturers of pharmaceuticals. State governments have clung to the power to regulate pharmacies of all kinds.
Other recent compounding pharmacy issues, where there have been contamination concerns, are, as noted by the New York Times and USA Today:

a) In August 2011, the FDA reported that repackaged injections of Avastin (bevacizumab) caused serious eye infections in the Miami, Florida area. A pharmacy had repackaged the Avastin from single-use vials into multiple single-use syringes, distributing them to multiple eye clinics, and infecting at least 12 patients. Some patients lost the remaining vision in the eye being treated.

b) From November 2011 to April 2012, 33 eye-surgery patients in seven states suffered a rare fungal eye infection tied to injectable drug products made by a compounding pharmacy in Ocala, Florida. Most of those patients suffered partial to severe vision loss.

c) In November 13 2012, it was reported that manufacturing problems were found at Ameridose, a Massachusetts company that makes injectable drugs.

Here is the list of all of Med Prep Consulting's products, all of which are being recalled:

Acetylcystiene vials

Alteplase syringe

Atropine syringe

Avastin syringe

Aztreonam syringe

Bacitracin vials

Bupivacaine Bag

Bupivacaine Syringe

Bupivacaine OnQ Pump

Calcium Gluconate Bag

Calcium Gluconate syringe

Cefazolin syringe

Cefazolin Bag

Cefepime syringe

Cefepime Bag

Cefotaxime syringe

Cefotetan syringe

Cefoxitin syringe

Ceftazidime syringe

Ceftazidime Bag

Ceftriaxone syringe

Ceftriaxone Bag

Cefuroxime syringe

Cefuroxime Bag

Clindamycin syringe

Darboepoetin (Aranesp) syringe

Dexamethasone Bag

Diltiazem Bag

Dobutamine Bag

Dobutamine syringe

Ephedrine syringes

Epinephrine Bag

Epinephrine Bag

Epinephrine syringe

Epoetin Alfa syringe

Esmolol syringes

Famotidine syringe

Fentanyl Citrate Bag

Fentanyl Citrate with Bupivacaine HCL Bag

Gentamicin syringe

Gentamicin Bag

Glycopyrrolate syringes

Granisetron syringe

Hectoral syringe

Heparin syringe

Heparin bag

Hydromorphone syringe

Hydromorphone Bag

Hydromorphone PCA syringe

LET Gel syringe

LET Soln syringe

Leukine syringe

Magnesium Sulfate bag

Meperidine Bag

Midazolam Bag

Midazolam syringe

Morphine Sulfate Bag

Morphine Sulfate syringe

Norepinephrine bag

Norepinephrine Syringe

Ondansetron Bag

Ondansetron syringe

Oxacillin syringe

Oxacillin Bag

Oxytocin bag

Palanosetron (Aloxi) syringe

Penicillin syringe

Penicillin Bag

Phenylephrine Bags

Phenylephrine syringes

Potassium Chloride Bag

Potassium Phosphate l bag

Ranitidine syringe

Rituxan syringe

Ropivacaine Bag

Ropivacaine OnQ Pump

Sodium Citrate syringe

Sodium Phosphate bag

Succinylcholine syringes

Sufentanil with Bupivacaine Bag

Timentin syringe

Tobramycin syringe

Zometa syringe
Posted by Tim Sandle

Studying the bacterial community of the skin

A study has been undertaken of the bacterial community of the skin. The research was undertaken by Elizabeth Grice of the National Institutes of Health (USA). Grice studied bacteria on 20 different body parts.

The research found that certain types of skin-dwelling bacteria thrive in warm, moist places like armpits and between toes. Others microorganisms prefer wide, dry expanses like the backside. The research also showed each person's collection of bacteria is unique -- like fingerprints. However, unlike fingerprints, the bacterial communities can change depending on your diet, environment, health, age and many other factors.

The research also showed that certain diseases, like diabetes, also affect the bacteria on the skin. A major complication of diabetes is sores, or ulcers, on the feet that never heal. Grice suspects that high blood sugar, which is known to change the skin's structure, likely encourages a specific subset of bacteria to grow.

For further details see BodyBacteria

Posted by Tim Sandle

Sunday 17 March 2013

Why The Swab Matters In Cleaning Validation

Cross-contamination with extraneous residues of any kind presents a safety risk to patients consuming the drug product. To explore the assessment of this risk and in a discussion on the importance of methods of detection for cleaning validation, Sandeep Kalelkar has written a comprehensive overview for Controlled Environments magazine.

An excerpt reads:

“Swabbing and rinsing are the two most common techniques used for sampling of such cleaned surfaces. Swabbing is a direct surface sampling method, while rinsing is an indirect method. In practice, physical access to surfaces and parts of equipment to be cleaned tends to drive the choice of sampling method. For example, swabbing would work particularly well in more restricted work areas such as isolators, hoods, and accessible corners of equipment, while rinsing would work best in pipes and longer tubes. In general, a combination of both is most desirable in order to accomplish the most comprehensive coverage of surfaces to be cleaned.”

To read the articles see Controlled Environments.

Posted by Tim Sandle

Saturday 16 March 2013

Formation of biofilms

Scientists at The Scripps Research Institute have unravelled a complex chemical pathway that enables bacteria to form clusters called biofilms. Such improved understanding might eventually aid the development of new treatments targeting biofilms.

Biofilm formation is a an important phenomenon that occurs when bacterial cells adhere to each other and to surfaces, at times as part of their growth stage and at other times to gird against attack. In such aggregations, cells on the outside of a biofilm might still be susceptible to natural or pharmaceutical antibiotics, but the interior cells are relatively protected. This can make them difficult to kill using conventional treatments.

Past research had also revealed that nitric oxide is involved in influencing bacterial biofilm formation. Nitric oxide in sufficient quantity is toxic to bacteria, so it's logical that nitric oxide would trigger bacteria to enter the safety huddle of a biofilm.

Many bacteria also have H-NOX domains, including key pathogens, so this seemed the best starting point for the investigation. From there, the team turned to genomic data. Genes for proteins that interact are often found adjacent to one another.

Based on this fact, the researchers were able to infer a connection between the bacterial H-NOX domain and an enzyme called histidine kinase, which transfers phosphate chemical groups to other molecules in signaling pathways. The question was where the phosphates were going.

To learn more, the researchers used a technique called phosphotransfer profiling. This involved activating the histidine kinase and then allowing them to react separately with about 20 potential targets. Those targets that the histidine kinase rapidly transferred phosphates to had to be part of the signaling pathway.

The experiments revealed that the histidine kinase phosphorylated three proteins called response regulators that work together to control biofilm formation for the project's primary study species, the bacterium Shewanella oneidensis, which is found in lake sediments.

Further work showed that each regulator plays a complementary role, making for an unusually complex system. One regulator activates gene expression, another controls the activity of an enzyme producing cyclic diguanosine monophosphate, an important bacterial messenger molecule that is critical in biofilm formation, and the third tunes the degree of activity of the second.

Lars Plate, Michael A. Marletta. Nitric Oxide Modulates Bacterial Biofilm Formation through a Multicomponent Cyclic-di-GMP Signaling Network. Molecular Cell, 2012

Posted by Tim Sandle

Friday 15 March 2013

Risk Management and Risk Assessment for Pharmaceutical Manufacturing

'Risk Management and Risk Assessment for Pharmaceutical Manufacturing' is a new e-book.

The book presents an overview of risk management and risk assessment for those working in the pharmaceutical and healthcare sectors. An understanding of risk management and risk assessment is today becoming a prerequisite for those working in quality control and quality assurance, and for those active in pharmaceuticals and medical devices, Quality Risk Management it is a mandatory requirement. The approach to risk assessment is examined through a number of case studies.

The book is available from Amazon U.S. and Amazon U.K., as well as other Amazon stores. The book contains over 200 pages and retails at under $25.

Posted by Tim Sandle

QbD and the New Process Validation Guidance

PharmaPro are hosting an interesting article by Bikash Chatterjee and Wai Wong, Pharmatech Associates on the subject of ‘QbD and the New Process Validation Guidance’.

The introduction to the article reads:

“Very simply, the aim of pharmaceutical development is to design a quality product and manufacturing process to consistently deliver the intended performance of a final therapeutic product.

To support a final quality assurance approach to manufacturing, it is the information and knowledge gained from pharmaceutical development studies and process characterization studies that lead to an effective quality control strategy, based on scientific understanding.

To that point, in January 2011 the FDA issued its new guidance on Process Validation (PV). The new PV guidance uses the basic principles of scientific understanding put forth in ICHQ8—the foundation of Quality by Design (QbD)—to establish process understanding and link it to product reproducibility. It effectively abandons the old concepts of demonstrating process validation and replaces it with a new, structured approach. It formalizes these principles by describing the level of product and process understanding necessary to satisfy the requirements of Stage 1 of the new PV guidance. To achieve this level of process understanding a framework that integrates product performance as part of process characterization is required. So simply put, the new PV guidance will make it much easier to justify moving toward QbD.

The challenge that many industry personnel face is bridging the gap between the former validation approach of “three batches and we’re done” to understanding how the new PV stages work together to establish process predictability.”

The article can be viewed free on line via PharmPro

Posted by Tim Sandle

Thursday 14 March 2013


A new edition of the Pharmacopeial Forum (vol. 39, No. 2) has been published. In the new edition, the following general chapters of interest:

Chapter 1229.4 Sterilizing Filtration of Liquids

(Revision proposal target, USP37-NF32 1S)

The current general chapter Sterilization and Sterility Assurance of Compendial Articles 1211 will be split into several individual chapters. This chapter provides an overview of (1) various factors that affect the filtration process, (2) filtration conditions, (3) validation, (4) the filter integrity test, (5) when to test integrity, (6) prefiltration bioburden control, (7) responsibilities of the filter manufacturer and user, and (8) troubleshooting the filtration process.

Chapter 1229.10 Radiation Sterilization

(Revision proposal target, USP37-NF32 1S)

This proposed chapter provides an overview of radiation sterilization and its validation, including dose setting, material compatibility, and dose verification.

Posted by Tim Sandle

Enhanced Sterility Assurance in Stopper processing

Sartorius have issued a white paper entitled “Enhanced Sterility Assurance in Stopper processing: A Unique System to Unload Stoppers from a Stopper Processing System”.

The abstract to the paper reads:

“Stoppers for pharmaceutical primary packaging must preserve the safety and efficacy of injectable drugs. Thus, before their intended use, these stoppers undergo multiple processing steps, including washing, rinsing, siliconization, steam sterilization and drying. Each step is critical to ensure the physical and mechanical properties of the stoppers by reducing particles, adding the appropriate silicon volume, sterilizing and avoiding re-contamination due to residual moisture. An additional critical step after the stopper processing is maintenance of closure integrity until filling in aseptic conditions. This paper discusses the validation of the transfer of stoppers from a stopper processing system, using a new aseptic transfer technology. It demonstrates that this technology maintains the sterility of the stoppers after their transfer into sterile single-use bags in an ISO Class 7 or 8 environment.”

To access the paper go to Pharmaceutical Technology

Posted by Tim Sandle

Wednesday 13 March 2013

Disinfectant Qualifications: Insight and Perspective

Disinfectant qualification studies play a key role in assuring that a company's clean room is sterile and within the prescribed U.S. Food and Drug Administration (FDA) standards. With clean room sterility of utmost importance, disinfectant qualification studies are valuable in analyzing and evaluating disinfectant effectiveness.

The CDC Handbook: A Guide to Cleaning and Disinfecting Cleanrooms

To examine this important subject further, Microtest have produced a white paper written by Deborah Ensign, Shawn Sherry, and Kate Bloomrose. The paper covers some of the basic areas.

To view the paper, go to Microtest

Posted by Tim Sandle

Cleanroom Technology (March 2013)

The latest edition of Cleanroom Technology has been issued (March 2013). In the current issue there is an article by Tim Sandle which reviews the twentieth anniversary of the Pharmaceutical Microbiology Interest Group (Pharmig):

Sandle, T. (2013). Twenty years of Microbiology, Cleanroom Technology, March 2013, pp24-25

The current issue also features articles on:
  • Safe handling of animal pathogens by David Crampton
  • Designing facilities for aseptic filling by Zhang Xiulan
  • Twenty years of microbiology by Tim Sandle
  • Building data from extemotolerant bacterial strains by C. Mossil-Eichinger and colleagues
  • And more…
For further details see Cleanroom Technology 

Posted by Tim Sandle

Tuesday 12 March 2013

Inspection of speciality compounding pharmacies

Following the fungal meningitis outbreak last fall that was linked to contaminated sterile drugs (NECC), the FDA has launched an inspection campaign of large specialty pharmacies. The inspections mid February and will continue over the next two months, covering about 30 facilities.

For further information see: Washington Post

Posted by Tim Sandle

Fungal cleaning enzymes

Prof. Dr. Dietmar A. Plattner, Dr. Klaus Piontek, and Eric Strittmatter from the Institute of Organic Chemistry of the University of Freiburg and their colleagues from research groups at the International Graduate School of Zittau of the University of Dresden have determined the three-dimensional atomic structure of fungal enzyme of this kind, a dye-decolorizing peroxidase (DyP).

For further details see:

E. Strittmatter, C. Liers, R. Ullrich, S. Wachter, M. Hofrichter, D. A. Plattner, K. Piontek. First Crystal Structure of a Fungal High-redox Potential Dye-decolorizing Peroxidase: SUBSTRATE INTERACTION SITES AND LONG-RANGE ELECTRON TRANSFER. Journal of Biological Chemistry, 2012; 288 (6): 4095 DOI: 10.1074/jbc.M112.400176

Posted by Tim Sandle

Clean Air and Containment Review #13

A new edition of Clean Air and Containment Review has been issued (issue 13). The latest journal features:
  • Control of laboratory air-change rates by Gordon P. Sharp
  • Developments in isolators for biotech based and potent drug substances by Volker Sigawarth and colleagues
  • Enhanced filtration technology, in relation to HEPA filters by Hugo Hemel
  • An update of the ISO 14644 revision process by Gordon Farquharson, Stephen Ward and Richard Roberts
  • An update of the ISO 14698 revision process by Tony Harrison
  • Application of Quality Risk Management to cleanroom design by Tim Sandle
  • An obituary of Willis Whitfield by Bill Whyte
  • A review of the new cleaning and disinfection handbook (edited by Tim Sandle) by James H Filer
  • And more…
For details see CACR.

The reference for my article is:

Sandle, T. (2013). Application of Quality Risk Management to cleanroom design, Clean Air and Containment Review, 13, pp24-25

Posted by Tim Sandle

Monday 11 March 2013

Antibiotic resistance: a "ticking time bomb"

The issue of growing resistance to antibiotics is a major global problem and should be ranked alongside threat of terrorism, according to the chief medical officer for England.
Antimicrobial resistance describes the ability of a microorganism to resist the action of antimicrobial drugs. This is important as it can make the treatment of infections more difficult and increase hospital costs, according to the U.K. Department of Health.
Antibiotic resistance is a serious and growing concern, with more microorganisms becoming resistant (the so-called ‘superbugs’ like MRSA) and fewer effective antibiotics being available, according to the World Health Organization (WHO). As an example, the WHO indicates that 150,000 deaths a year are caused by multi-drug resistant tuberculosis.
One of the main causes, the U.S. Center for Disease Control notes, has been down to overuse of antibiotics, often in cases where none were needed, leading to the adaptation of microorganisms to become resistant.
To highlight this concern Professor Dame Sally Davies, the U.K. government's chief medical officer for England has said, according to the BBC: “If we don't take action, then we may all be back in an almost 19th Century environment where infections kill us as a result of routine operations. We won't be able to do a lot of our cancer treatments or organ transplants.”
She went on to make a point about the lack of new drug development on the part of pharmaceutical companies: “We haven't had a new class of antibiotics since the late 80s and there are very few antibiotics in the pipeline of the big pharmaceutical companies that develop and make drugs.
“We haven't as a society globally incentivised making antibiotics. It's quite simple - if they make something to treat high blood pressure or diabetes and it works, we will use it on our patients everyday. Whereas antibiotics will only be used for a week or two when they're needed, and then they have a limited life span because of resistance developing anyway.”
Professor Davies has expanded upon these issues in her annual report to the U.K. government.
A number of global bodies are attempting to work with ‘big pharma’ to develop new antibiotics, such as the Innovative Medicines Initiative (IMI) in Europe, which is a public-private initiative aiming to speed up the development of better and safer medicines for patients; as well as initiatives by the U.S. National Institutes of Health.
What remains of concern is that as bacterial antibiotic resistance continues to exhaust the supply of effective antibiotics, a global public health disaster could arise within the next decade. It is therefore a serious matter for governments, the medical profession, the pharmaceutical industry and individuals.

Posted by Tim Sandle

Death cap mushroom and cancer treatment

The death cap mushroom (Amanita phalloides) contain α-amanitin, one of the most deadly poisons found in nature. However, scientists from three German research centers are using that toxin for good—combating pancreatic cancer.

In the Journal of the National Cancer Institute, researchers attached α-amanitin to an antibody that binds to EpCAM, a cell surface protein abundant in human cancers. In a dish, the poison-loaded antibody arrested the growth of pancreatic, colorectal, breast, and bile duct cancer cell lines. In mice transplanted with human pancreatic tumors, the treatment resulted in tumor regression in 9 of 10 mice.
Alpha-amanitin is an ideal toxin for the treatment, the authors noted, because it is small enough not to be recognized as foreign by immune cells, but robust enough to hitch a ride on the antibody.

For more details, see the Fierce Biotech press release.

Posted by Tim Sandle

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