New edition of the USP

A new edition of the USP has recently been issued: USP36-NF31. The changes of interest are:

General Chapters

Listed are items in which changes have been made to existing official text.

General Tests and Assays

Chapter 1        Injections

Revision to the following sections: Foreign and Particulate matter.

Physical Tests and Determinations

Chapter788     Particulate Matter in Injections

Revision to the following sections: Introduction and Method 1 Light Obscuration Particle Count Test.

Chapter 921    Water Determination

Revision to the following sections: Method I (Titrimetric and Method II (Azeotropic – Toluene Distillation), General information.

Chapter1051   Cleaning Glass Apparatus

Introduction and appendix have been added.

Chapter 1197 Good Distribution Practices for Bulk Pharmaceutical Excipients [NEW]

NF31: Monographs

Caprylic Acid [NEW] (Octanoic acid)

For further details, see USP.

Posted by Tim Sandle

ATCC® Bacteriology Culture Guide

The American Type Culture Collection (ATCC) have produced a useful guide containing general technical information regarding bacterial growth, propagation, preservation, and application.

The guide is available to those who register on the ATCC website. For details go to ATCC.

Posted by Tim Sandle

Antibiotic Resistance Using Crystallography

Scientists at the University of Bristol, together with collaborators at the University of Aveiro, Portugal, have solved the structure of an enzyme that breaks down carbapenems , antibiotics 'of last resort' which, until recently, were kept in reserve for serious infections that failed to respond to other treatments.

Carbapenemases are members of the group of enzymes called beta-lactamases that break down penicillins and related antibiotics.

Using molecular dynamics simulations, Professor Adrian Mulholland in the School of Chemistry and Dr Jim Spencer in the School of Cellular and Molecular Medicine, showed how a particular type of carbapenemase enzyme reorients bound antibiotic to promote its breakdown and render it ineffective.

In a study published in the Journal of the American Chemical Society (JACS), the scientists combined laboratory experiments with computer simulations to investigate how one particular type of carbapenemase recognises and breaks down antibiotics.

Using X-ray crystallography, they obtained two 'snapshots' of the carbapenemase in the act of breaking down a carbapenem antibiotic. This static structural information was used as a starting point for simulations that modelled the motions of the enzyme and the bound antibiotic.

The simulations showed how the carbapenemase reorients the drug to promote its breakdown. In beta-lactamases that cannot break down carbapenems, this rearrangement cannot happen, and so the enzyme cannot break down the antibiotic. Knowing this should help in designing new drugs that can resist being broken down.

For further details, see:

Fátima Fonseca, Ewa I. Chudyk, Marc W. van der Kamp, António Correia, Adrian J. Mulholland, James Spencer. The Basis for Carbapenem Hydrolysis by Class A β-Lactamases: A Combined Investigation using Crystallography and Simulations. Journal of the American Chemical Society, 2012; 134 (44)

Posted by Tim Sandle

Pharmaceutical Water Guideline (WHO)

An update from the European Compliance Academy on the revised WHO standard for pharmaceutical water.

The current TRS 970 of the WHO comprises an updated version of the guideline regarding the manufacture and distribution of water for pharmaceutical use. The range of the guideline's scope has been narrowed by excluding the processing small amounts of water in pharmacies. A key change is the indication that the design of a water system is important for avoiding microbiological growth in the system (in the previous version only the sanitisation was mentioned as control measure). The authors also emphasise the importance of the appropriate capacity to ensure a sufficient re-circulation.

A further change is that the pharmaceutical manufacturer must be responsible for ensuring that the feed water has drinking water quality. If the in-coming water is not of a suitable quality, the manufacturer must take suitable measures in a step prior to the actual treatment to guarantee this quality.

With regard to purified water (AP) the revision now mentions the possible treatment components (reverse osmosis and EDI). The amendment states (similar to the USP) that warning limits are supposed to be based on operational experience.

To view the revised standard, go to: ECA

Posted by Tim Sandle

Pharmeuropa 25.2

A new edition of Pharmeuropa: 25.2, has recently been published. This is the forum where draft European Pharmacopeia monographs are published for public comment.

If no further revision is required the draft monograph is proposed to the European Pharmacopoeia Commission if adopted an implementation date is given and this is about one year after the adoption of the monograph. The monograph is then published in the European Pharmacopoeia (or supplement). The monograph is published about 6 months after adoption. Therefore draft text appearing in Pharmeuropa may not become official for up to 2 years. Those monograph’s adopted will be highlighted in reviews of the European Pharmacopoeia or supplements.

In the new edition, there is one change of interest:

Monograph 3.2.1.        Glass Containers for Pharmaceutical Use

The main changes are:

Production: a section has been introduced to address the risk related to potential delamination of glass containers. This is done by raising awareness of the pharmaceutical manufacturers of the factors contributing to the phenomenon which resulted in a number of recalls. Although only a very small number of containers was affected it is an important factor to be considered for both the glass manufacturers and the pharmaceutical users.

Harmonisation with ISO 4802 – 1 and 4802 - 2: adjustment was made to avoid ambiguities with ISO. This includes the addition of an additional volume specification for containers of a volume of 2 to 3 mL in Table 3.2.1-3 and Table 3.2.1-7.

Test for surface hydrolytic resistance – determination by flame spectrometry: some editorial modifications were made to clarify the text.

Hydrolytic resistance of glass grains: alternative grinding device introduced to include state of the art equipment resulting in increased reproducibility of sample preparation.

Need for control of specific components that may be toxic for chronic use and vulnerable patient groups: this information was already proposed in a previous publication in Pharmeuropa 24.2

For further details, see EDQM.

Posted by Tim Sandle

Disinfectant validation

Disinfectants used in hospitals and biopharmaceutical facilities should be selected with care, not least to show that they are compatible with the detergents used to clean, with the surfaces intended to be disinfected and with each other. In an exclusive extract from ‘The CDC Handbook: A Guide to Cleaning & Disinfecting Cleanrooms’, Dr Tim Sandle has outlined the essential requirements for the validation of disinfectants, focusing upon European standards.

The article focuses on the European approach to disinfectant validation. The standard European approach for disinfectant validation consists of a basic suspension test, a quantitative suspension test (with low and high levels of organic material added to act as ‘interfering substances’) and a two part simulated-use surface test.

The extract has been published in the journal EuropeanMedical Hygiene. To subscribe to the journal go to:

If anyone would like a copy of the article, please contact Tim Sandle.

The reference is:

Sandle, T. (2012). Ensuring Contamination Control: The validation of disinfectants, European Medical Hygiene, November 2012, pp33-39

Posted by Tim Sandle

Antifungal polyvinylidene fluoride (PVDF) in cleanrooms

High technology cleanroom environments often contain polymeric sheets, coatings, wall coverings, and polymeric foam for insulation. These are used to create lightweight structures, walls, partitions, ceilings, and pipe and ducting insulation. Many of these materials are antifungal, due to low surface energy.

Such material can be assessed using the ASTM G21-96 (2002), Standard Practice for Determining Resistance of Synthetic Polymeric Materials to Fungi.

In looking at this further, Ron Partridge has written an article examining the latest developments and standards. It can be found on-line, hosted by Controlled Environments, here.

Posted by Tim Sandle

Copper can destroy norovirus

New research from the University of Southampton shows that copper and copper alloys will rapidly destroy norovirus, the highly-infectious sickness bug. Initial research suggest that norovirus van be rapidly destroyed on copper and its alloys, with those containing more than 60 per cent copper proving particularly effective. The contamination model used was designed to simulate fingertip-touch contamination of surfaces.

Professor Bill Keevil, Chair in Environmental Healthcare at the University of Southampton and lead researcher, presented his work at the American Society for Microbiology's 2013 General Meeting.

Norovirus can remain infectious on solid surfaces and is also resistant to many cleaning solutions. Potentially copper alloy surfaces can be employed in high-risk areas such as cruise ships and care homes, where norovirus outbreaks are hard to control.

For further details, see the University of Southampton

Posted by Tim Sandle

IEST: contamination control guidelines

Not directly related to pharmaceuticals, but possible of wider interest those involved with controlled environments.

The Institute of Environmental Sciences and Technology (IEST) has released a new Recommended Practice, IEST-RP-CC046.1: Controlled Environments (Aerospace, Non-cleanroom), which contains contamination control guidelines from piece-part acquisition to product delivery.

The guideline contains contamination control criteria to support successful performance of high-reliability products and associated subassemblies, which are not required to be produced in cleanrooms. A key factor in protecting such products from contamination is the development of a Contamination and Foreign Object Damage (FOD) Control Program.

This first-edition Recommended Practice is focused on the aerospace industry and provides a minimum set of requirements for a basic contamination control programme, which could be tailored to specific products and processes.

“This Recommended Practice provides a set of basic guidelines for producing high-reliability products using affordable methods to control production environments and prevent contamination,” said Rick George, Chairman of the IEST Working Group that produced this document. “These guidelines, which have been sorely lacking in many industries, make it easier for smaller companies to provide clean products in a cost-effective manner.”

Using a “clean as you go” approach, IEST-RP-CC046.1 sets out standardised procedures to mitigate contamination during production operations and preserve product cleanliness through assembly, test, storage, and transportation.

The goals of this approach are to: prevent intrusion of contaminants from outside the controlled area; minimise the generation of contaminants within the controlled area; and remove contaminants before they can attach to critical surfaces.

For further details see IEST

Posted by Tim Sandle

ECHA authorisation list: cleanroom chemicals

Chemicals used in cleanrooms have been added to the European Union’s ‘authorisation’ list over environmental health concerns.

A listing requires cleanrooms wanting to use these chemicals to seek permission from the European Commission, advised by the European Chemical Agency (ECHA). The chemicals are potassium dichromate and trichloroethylene, which will require authorisation for use from September 2017 and April 2016 respectively.

Potassium dichromate, used to make chromic acid for cleaning glassware and as an oxidising agent in various laboratories, was listed for being carcinogenic, mutagenic and toxic to reproduction. Trichloroethylene, used for cold-cleaning of fabricated metal parts and as a solvent in vapour-degreasing, is a carcinogen.

ECHA has clarified that cleanrooms applying for authorisation can continue using these chemicals after these ‘sunset dates’ while waiting for a Commission decision.

Source: Cleanroom Technology

Posted by Tim Sandle

Main Street Family Pharmacy in Tennessee

The U.S. Food and Drug Administration (FDA) has identified bacterial and fungal growth in samples from two unopened vials of preservative-free (PF) methylprednisolone acetate (MPA) 80 mg/mL, 10mL vials form Main Street Family Pharmacy.

The microbial growth was seen in samples from two separate lots (batches). Additional samples and lots of PF MPA are still under evaluation, as well as other sterile products produced by Main Street. FDA, in partnership with the U.S. Centers for Disease Control (CDC), is working to identify the exact species of fungus and bacteria observed in the vials. FDA has received reports of adverse events, including skin and soft tissue abscesses. To date, FDA is not aware of any cases of meningitis associated with Main Street’s preservative free methylprednisolone acetate for injection.

The FDA asks health care providers and consumers to report adverse events or quality problems experienced with this or any Main Street products to the FDA’s MedWatch Adverse Event Reporting program
Posted by Tim Sandle

Contamination Control in Healthcare Product Manufacturing

A new PDA / DHI book of interest has been published. The book is titled ‘Contamination Control in Healthcare Product Manufacturing, Volume 1’ and it has been edited by Russell Madsen, Jeanne Moldenhauer.

The description for the book reads:

“Contamination Control in Healthcare Product Manufacturing, Volume 1, edited by Russell E. Madsen and Jeanne Moldenhauer, is primarily focused on microbiological contamination and the methods used to monitor and control it, a secondary focus looks at chemical contamination that may result from the use of cleaning and disinfecting agents. There is something for almost everyone who has responsibility for developing or using microbiological contamination control programs and systems.

In this first book of the contamination control series, you will be provided with a wealth of information that can aid you in understanding the sources of contamination, types of control measures that can be used, methods to use when contamination occurs and regulatory expectations for management of these systems.”

The chapters which make up the book, written by leading industry experts, are:

1.Introduction by Russell E. Madsen and Jeanne Moldenhauer

2.The Contamination Control Plan in Facility Validation by Scott Sutton

3.Facility Design and Control: Materials and Design by Gary Devloo

4.Facility Design and Control: HVAC by John Pinto

5.Facility Design and Control: Personnel by Anne Marie Dixon

6.Facility Design and Control: Cleaning and Sanitization by Anne Marie Dixon

7.Single-Use Systems for Contamination Control by Maik W. Jornitz

8.Selecting an Appropriate Process Cleaning Detergent by Mark Compo

9.Disinfectant Qualification by Ziva Abraham

10.Environmental Monitoring for Non-Sterile Operations by Miriam Rozo

11.Fungal and Bacterial Spores: Contamination and Disinfection by Jim Polarine, Carol Bartnett and Dan Klein

12.Microbial Control: Mold by Brian G. Hubka

13.Sterility Test Failure Investigations by Jeanne Moldenhauer

14.Endotoxins by Karen Zink McCullough

15.An Audit Approach to Address Microbial Contamination in Process Equipment by Paul Lopolito and Elizabeth Rivera

16.Impact of Biofilms in Contamination Control by Lucia Clontz

17.Deviations and Investigations by Frank Settineri

18.Contamination Control Risk Assessment by Tim Sandle

19.The Role of In-House Microbial Isolates in Contamination Control by Robert Westney

For further details about the publication, see the PDA.

Posted by Tim Sandle

How to Write Like a Scientist

A shorter blog post. Adam Ruben has written an amusing, but equally very insightful article titled 'How to Write Like a Scientist'. It is hosted by Science.

Here is an extract:

"Why can’t we write like other people write? Why can’t we tell our science in interesting, dynamic stories? Why must we write dryly? (Or, to rephrase that last sentence in the passive voice, as seems to be the scientific fashion, why must dryness be written by us?)"

Read the full article here: Ruben article
Posted by Tim Sandle

USP General Chapters on Sterilization

Two new proposed sterilisation chapters have appeared in the Pharmacopeial Forum 39 (3) for comments.

These are:

USP - 1229.7 Gaseous Sterilization

The use of sterilizing gases for the preparation of materials and equipment is in widespread application for items that are susceptible to damage by heat or radiation processes. Many polymeric materials, especially medical devices, are sterilized in this manner, as is non-pressure-rated process equipment.

As outlined in Sterilization of Compendial Articles 1229, the chapter addresses such processes as ethylene oxide, ozone, and chlorine dioxide. The majority of gas sterilization processes employ ethylene oxide (EtO), and procedures for use with other gases generally are patterned after EtO practices.

The chapter also addresses validation requirements and routine process control.

USP – 1229.8 Dry Heat Sterilization

Dry heat sterilization is a process employed for heat-stable items that are unsuited for steam sterilization because of either an absence of water (nonaqueous liquids and powders) or requirements for absolute dryness following processing (product contact parts for nonaqueous products).

This chapter addresses the sterilisation control cycle, validation requirements, biological indicators and routine process controls.

For further details, see the PF.

Posted by Tim Sandle

New compounds to curb Staph infection

Writing online in the Journal of the American Chemical Society, a group led by University of Wisconsin-Madison chemistry professor Helen Blackwell describes agents that effectively interfere with the "quorum sensing" behavior of Staphylococcus aureus.

The research team identified peptide-based signaling molecules that effectively outcompete the native molecules the bacterium uses to communicate and activate the genes that cause disease.

Bacteria use quorum sensing to assess their population density and coordinate certain behaviors. They do so through the use of pheromone-like chemicals, which bind to receptors either in the bacterial cell or on its surface and tell it if there are enough companion bacteria around to switch on genes that perform certain functions. In the case of Staphylococcus aureus, quorum sensing activates toxin production, manifesting disease in the host.

Interfering with bacterial quorum sensing to stymie disease is considered a promising new antibiotic strategy.

For further details, refer to the following paper:

Yftah Tal-Gan, Danielle M. Stacy, Mary K. Foegen, David W. Koenig, Helen E. Blackwell. Highly Potent Inhibitors of Quorum Sensing in Staphylococcus aureus Revealed Through a Systematic Synthetic Study of the Group-III Autoinducing Peptide. Journal of the American Chemical Society, 2013

Posted by Tim Sandle