Pharmaceutical Microbiology

Developments in regulatory standards Part 6

timsandle@btinternet.com (Tim Sandle) — Fri, 10 Feb 2012 06:00:07 PST

Developments in regulatory standards Part 6

By Tim Sandle

The sixth in our series on regulatory issues for 2012 looks at EMA / EU GMP.

Guideline on similar biological medicinal products containing monoclonal antibodies

The EMA have issued a new draft document: “Guideline on similar biological medicinal products containing monoclonal antibodies.”

The introduction reads:

"This guideline lays down the non-clinical and clinical requirements for monoclonal antibody (mAb) containing medicinal products claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological requirements and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as pharmacovigilance aspects."

The draft can be accessed, as a pdf document, here: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf

EU GMP Updates: Chapter 4 (Documentation) and Annex 11 (Computerised Systems)

Chapter 4 (Documentation) and Annex 11 (Computerised Systems) have been revised by the European Commission. The new versions were published on 03 Jan 2011. Both came into operation on 30 June 2011.

A summary of the reasons for the changes are

Annex 11: the Annex has been revised in response to the increased use of computerised systems and complexity of these systems. Consequential amendments have been made to Chapter 4 of the GMP Guide.
Revision of the Annex has resulted in a restructuring of the document into the following five areas (and 17 sub-chapters).Principles, General, Project Phase, Operational Phase and Glossary.
Chapter 4: the sections on 'generation and control of documentation' and 'retention of documents' have been revised, in light of the increasing use of electronic documents within the GMP environment.

The contents are:

· General: the requirements apply to all forms of document media types like paper, electronic documentation, photographic media or hybrid types.

· Quality Manual System: The QMS should fully define documents and media. As part of the QMS an inventory of documents should be maintained.

· The Major types of GMP documentation required are now listed as:

· Site Master File

· Instructions:

· Specifications

· Manufacturing Formulae, Processing, Packaging and Testing Instructions

· Procedures

· Protocols

· Technical Agreements

· Records/Reports:

· Records

· Certificates of Analysis

· Reports

· Retention Periods: The requirement on retention periods are now given in more detail.

· Line Clearance: A formal line clearance has been introduced.

· Acknowledgements of new developments: An acknowledgement of new initiatives such as PAT (process analytical technology) or real time testing.

· Activities of the Qualified Person: The role of the QP is explained in more detail.

· More detailed SOP list: The list of policies, procedures, protocols, reports and associated records has been amended.

· Logbooks: It has been emphasised that logbooks are expected for critical analytical testing equipment.

European Clinical Trials.

For the first time, the European Medicines Agency (EMA) has opened its clinical trials register to the public. Certain protocol-related information on trials conducted in the EU are now available.

The Clinical Trials register contains information about clinical trials authorised in the EU, whether they take place in one Member State or several. It includes clinical trials conducted by both industry and research. The register also includes the clinical trials contained in a Paediatric Investigation Plan – the research and development program that aims to generate the data required to authorise a medicinal product for use in children. The clinical trials contained in such a Plan are published even if they are performed outside the EU. However, positive and negative outcomes of the studies will be added at a later point in time. Also, the register is not complete at the moment. After completion by the EMA, the register will cover all clinical trials conducted in the European Union and all paediatric studies. Every year approximately 4,000 clinical trials are authorised in the EU. As most last 2 to 3 years, this means that around 10, 000 trials are ongoing at any given time.

The European Medicines Agency is responsible for the day-to-day management of the online register. The sponsor of the clinical trial provides and updates the information in the register via the national competent authority of the country, or countries, in which it is being conducted. The register is part of the overarching EU public database EudraPharm, which also centralizes information on medicines authorised by the EU, such as the patient information leaflet.

Good distribution practice (GDP) – review of deficiencies

The European Commission has revised the Good Distribution Practice (GDP) guidelines in line with the falsified medicines legislation and they have been published for consultation. A draft document has recently been issued (21 July 2011).

The stated reasons for change are:

"Reasons for change: The content of the Guidelines on Good Distribution Practice published in 1994 is no longer adequate. It needs to be reviewed to take into account advancements of practices for an appropriate storage and distribution of medicinal products in the European Union. Moreover, it should take into account the amendments to the Community Code which have been introduced with Directive 2011/62/EU of the European Parliament and of the Council amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products"

The document can be viewed here (as a pdf): http://ec.europa.eu/health/files/eudralex/vol-4/2011-07_gdpguidline_publicconsultation.pdf

Comments and suggestions are invited by 31 December 2011 and should be sent by email to:

SANCO-gmp@ec.europa.eu

Posted by: Dr. Tim Sandle

Developments in regulatory requirement Part 5

timsandle@btinternet.com (Tim Sandle) — Thu, 09 Feb 2012 06:30:02 PST

Developments in regulatory requirement Part 5

By Tim Sandle

The fifth part of the regulatory watch series looks at developments with the ISO (International Standards Organization), with a focus on cleanrooms.

ISO

Revision of cleanroom standards

The main cleanroom standard: ISO 14644, is undergoing revision and that the drafts were issued for public comment during 2011.

The ISO 14644 standard is made up of seven parts. The first two parts are the ones which are being revised, namely

ISO 14644-1 Cleanrooms and associated controlled environments: Part 1: Classification of air cleanliness by particle concentration
ISO 14644-2 Cleanrooms and associated controlled environments: Part 2: Specifications for monitoring and periodic testing to prove continued compliance with ISO 14644-1

The most significant changes with respect to these two standards are:

The Upper Confidence Limit calculation and Student ‘T’ Test are removed
The ‘square root rule’ for calculating the number of sample locations for classification has been removed
A new table has been added to determine the number of sample locations for classification according to the size of the area to be classified
Normative reference to ISO 21501-4 is now included, making compliance with ISO 21501-4 a requirement (ISO 21501-4 provides a calibration procedure and verification method for particle counters used to classify and monitor cleanrooms)
The Air Cleanliness Classification Table defining the maximum allowable number of particles for each ISO class has been modified. Most significantly to the pharmaceutical and healthcare industries, reference to the number of particles >5micron has been completely removed for ISO Class 5 (significant because EU GMP Annex 1 refers to particles 5micron for Grade A conditions and refers to this being equivalent to ISO Class 4.8 and, although the FDA cGMP does not refer to 5micron particles, it does refer to ISO Class 5 as being the environment for aseptic sterile manufacturing, thus implying that the area should attain the related 5micron cleanliness)

Particle counters and ISO 21501

The ISO standard for the calibration of particle counters (ISO 21501) has been out since 2007. However, it has not been mandatory to implement given no direct link with GMP. However, should ISO 14644 be updated the update will include a requirement for all particle counters to be calibrated to ISO 21501. And since ISO 14644 is mentioned in the EU GMP Guide and in the FDA 2004 guide to aseptic filling it could become a regulatory requirement.

ISO 21501 is important as it will feature in the new ISO 14644 and thus be subject to regulatory inspection. ISO 21501 Part 4 states:

"Instruments that conform to this part of ISO 21501 are to be used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO 1464401"

ISO 21501 was issued in 2007. Hitherto the application of the standard has been relatively slow. This is likely to change once the revised cleanroom classification standard is issued.

ISO 21501 sets out the tests required for the calibration of particle counters. These tests are:

Size calibration
Verification of size setting
Counting efficiency
Size resolution
False count rate
Concentration limit
Sampling flow rate
Sampling time
Sampling volume

The only means by which a particle counter used in pharmaceutical grade cleanrooms can be calibrated (where the lowest counted particle size is 0.5 microns) is by using a particle counter which can accurately count as low as 0.3 microns.

Although the standard is a considerable improvement on what has been in place previously, it does pose an obsolescence threat to older models of counter as many will not meet the new standard. This will become a problem for those who need to meet GMP regulations for 2011.

ISO/WD 14644-NN Cleanrooms and associated controlled environments — Part NN Classification of air cleanliness by nanoscale particle concentration

A new cleanroom standard, primarily aimed at the electronics industry, is in development. The draft standard went out for public comment in the summer of 2011, through different national standard bodies.

Posted by: Dr. Tim Sandle

Developments in Regulatory Requirements Part 4

timsandle@btinternet.com (Tim Sandle) — Thu, 09 Feb 2012 04:00:07 PST

Developments in Regulatory Requirements Part 4

By Tim Sandle

The fourth part of this week's series on regulatory updates looks at pharmacopeial harmonization.

The Pharmacopoeial Discussion Group (PDG) [European Pharmacopoeia (EP), Japanese Pharmacopoeia (JP) and United States Pharmacopeia (USP)] met on June 14-15, 2011 in Cincinnati, Ohio, USA.

At present, 28 of the 35 General Chapters and 41 of the 62 excipient monographs of the current work programme have been harmonised.

The General Chapter for Microcalorimetry is newly harmonized. Revised General Chapters include Bacterial Endotoxins and Bulk and Tapped Density. Excipient signoffs include revisions to Benzyl Alcohol, Potato Starch, Wheat Starch, Calcium Phosphate Dibasic, and Calcium Phosphate Dibasic Anhydrous monographs. The latter four revisions are the outcome of PDG’s review of previously harmonised excipient monographs.

At the Ohio meeting the three pharmacopoeias discussed other topics, including microbiological limits, additives in excipients, and metal impurities. Also, PDG decided to add the Isomalt monograph to its work programme.

The most recent face-to-face PDG meeting was hosted by EDQM on November 8-9, 2011 in Strasbourg, France.

Posted by: Dr. Tim Sandle

Pharmaceutical companies join forces to defeat 10 neglected tropical diseases

timsandle@btinternet.com (Tim Sandle) — Wed, 08 Feb 2012 09:00:05 PST

Major pharmaceutical companies are working with the ll & Melinda Gates Foundation and the World Health Organization to tackle tropical diseases. The companies include Pfizer, Sanofi and GlaxoSmithKline.

The aim is to eliminate 10 neglected tropical diseases (NTDs) by 2020. The group will aim to eliminate lymphatic filariasis (elephantiasis), guinea worm, blinding trachoma, sleeping sickness and leprosy, and control a further five diseases—soil transmitted helminthes (intestinal worms), schistosomiasis, river blindness, Chagas, and visceral leishmaniasis. These NTDs are estimated to affect more than one billion people in developing countries.

In a press statement Dr. Margaret Chan, director–general of WHO stated:

“The efforts of WHO, researchers, partners, and the contributions of industry have changed the face of NTDs. These ancient diseases are now being brought to their knees with stunning speed. With the boost to this momentum being made today, I am confident almost all of these diseases can be eliminated or controlled by the end of this decade.”

According to the statement, companies will donate an average of 1.4 billion treatments each year, while new collaborative R&D and access agreements will provide access to compound libraries that is expected to lead to new treatment options.

For more details, see the Gates Foundation Press Release.

Posted by: Dr. Tim Sandle

Developments in Regulatory Requirements Part 3

timsandle@btinternet.com (Tim Sandle) — Wed, 08 Feb 2012 06:30:00 PST

Developments in Regulatory Requirements Part 3

By Tim Sandle

This is the third article in a series looking at recent regulatory changes and some of those which are expected to emerge during 2012.

This post focuses on the FDA.

FDA

FDA joins PIC/S

From 1st January 2011 the FDA became a member of the PIC/S (Pharmaceutical Inspection and Co operation Scheme).

The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) are two international instruments between countries and pharmaceutical inspection authorities. The PIC/S is meant as an instrument to improve co-operation in the field of Good Manufacturing Practices between regulatory authorities and the pharmaceutical industry.

In relation to PIC/S, a meeting in May 2011 tabled the possibility of PIC/S extending to GDP (Good Distribution Practice) as well as GMP (Good Manufacturing Practice). A decision will be taken towards the end of 2011.

Advancing Regulatory Science for Public Health

The FDA has released a White Paper on Regulatory Science. The objective is:

“This document outlines a broad vision for advancing regulatory science and unleashing its potential to improve public health. It discusses the role of the FDA, working with partners, to strengthen the field, both within the agency and throughout the Nation.”

Recent breakthroughs in science and technology — ranging from sequencing of the human genome to advances in the application of nanotechnology to new medical products — have the potential to transform our ability to prevent, diagnose and treat disease. These developments will result in moving treatment strategies towards approaches that are tailored or personalized to individual patients, thus maximizing the benefit of treatments while decreasing their safety risks. Similarly, advances in research and information technologies are enabling us to more efficiently identify microbial pathogens, track food contamination outbreaks and determine where foods and other FDA-regulated products are produced or manufactured, how they are transported, where they go and who uses them. These tools also can play an important role in preventive health by enabling more comprehensive immunization strategies, especially in the face of emerging pandemics.

Here is the Table of Contents.

Executive Summary
The Promise of Regulatory Science
Accelerating the Delivery of New Medical Treatments to Patients
Improving Pediatric and Child Health
Protecting Against Emerging Infectious Diseases and Terrorism
Enhancing Safety and Health Through Informatics
Protecting the Food Supply
Modernizing Safety Testing
Meeting the Challenges for Regulating Tobacco
A Collaborative Implementation Framework

http://www.fda.gov/ScienceResearch/SpecialTopics/RegulatoryScience/ucm228131.htm

FDA Guidance for Industry "ANDAs: Impurities in Drug Products"

The FDA have revised the following guidance document: Guidance for Industry "ANDAs: Impurities in Drug Products".

The purpose of the document is to provide:

"....recommendations on what chemistry, manufacturing, and controls (CMC) information sponsors should include regarding the reporting, identification, and qualification of impurities that are classified as degradation products in drug products when submitting:

Original abbreviated new drug applications (ANDAs). ANDA supplements for changes that may affect the quantitative or qualitative degradation product profile

The guidance also provides recommendations for establishing acceptance criteria for degradation products (specifically, degradation products of the active ingredient or reaction products of the active ingredient with an excipient(s) and/or immediate container/closure system) in generic drug products. The guidance will replace an existing 1998 draft guidance of the same name."

The revised document can be found as a pdf here: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072861.pdf

FDA Blood Guidance Update

The FDA have issued a Guidance for Industry entitled: “Lookback” for Hepatitis C Virus (HCV): Product Quarantine, Consignee Notification, Further Testing, Product Disposition, and Notification of Transfusion Recipients Based on Donor Test Results Indicating Infection with HCV.

According to the FDA: "Chronic hepatitis due to HCV is a major health problem in the

U.S.

The infection is usually clinically silent until the liver is seriously damaged. As a result, infected people usually are unaware of their disease. Although transfusion-transmitted infections account for only a very small proportion of HCV infections, it is possible to identify and “lookback” at prior donations that might have been collected during the “window period.”"

To review the document, go to: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm078828.pdf

FDA draft guidance: Non-Penicillin Beta-Lactam Risk Assessment: A cGMP Framework

The FDA have recently issued a draft guidance paper concerning cross contamination during pharmaceutical processing: 'Non-Penicillin Beta-Lactam Risk Assessment: A cGMP Framework'. The paper is dated March 2011.

The introduction to the document reads:

"This guidance describes the importance of implementing appropriate steps during the manufacturing process to prevent cross-contamination of finished pharmaceuticals and active pharmaceutical ingredients (APIs) with non-penicillin beta-lactam antibiotics. This guidance also provides information regarding the relative health risk of, and the potential for, cross reactivity in the classes of sensitizing beta-lactams (penicillins and non-penicillin beta-lactams). This guidance is intended to assist manufacturers in assessing whether separate facilities should be used based on the relative health risk of cross-reactivity."

The guideline can be found here: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM246958.pdf

FDA: Changes to the Sterility Test

The latest edition of the Federal Register (Vol. 76, No. 119 / Tuesday, June 21, 2011) contains a very important announcement about the sterility test and represents, should the proposal in the Register pass, mark a step forwards towards the adoption of rapid and alternative microbiological methods.

In summary, the changes are that the CFR be updated:

Elimination of specified sterility test methods, culture media formulae (or formulations), and culture media test requirements;
Elimination of specified membrane filtration procedure requirement for certain products;
Elimination of specified sterility test requirements for most bulk material;
Modification of the repeat sterility test requirements, so that repeat tests would occur only once for each lot.
Replacement of the storage and maintenance requirements for cultures of test organisms used to determine the ‘‘growth-promoting qualities’’ of culture media with: (1) Validation requirements specifying that any sterility test used is able to consistently detect the presence of viable contaminating microorganisms and (2) verification of ‘‘growth promoting properties’’ 6 or microorganism-detection capabilities of test and test components;
Replacement of the sample size or amount requirement with a requirement that the sample be appropriate to the material being tested;
Replacement of the Interpretation of test results paragraph under § 610.12(c) with a requirement that manufacturers establish, implement, and follow written procedures for sterility testing that describe, at a minimum, the test method used, the method of sampling, and the written specifications for acceptance or rejection of each lot; and
Simplification of the Exceptions paragraph under § 610.12(c).

To view the Register, go to (opens as a pdf): http://www.gpo.gov/fdsys/pkg/FR-2011-06-21/pdf/2011-15346.pdf

In addition CBER (Center for Biologics Evaluation & Research) has issued a poster which considers rapid sterility testing. This follows the proposal by the FDA to update CFR 21.610 on the sterility test.

The poster, written by Seema Parveen, Simleen Kaur, James L. Keeny, William M. McCormick, Rajesh K. Gupta at the Center for Biologics Evaluation and Research, FDA, Rockville, MD, informs that “Researchers in the Division of Product Quality (DPQ) in the Office of Compliance and Biologics Quality (OCBQ) are working to resolve this problem by evaluating rapid microbial methods that significantly reduce the time needed for sterility testing of biologicals”.

In the poster, the researchers outline how they have begun to evaluate different sterility test systems. This was by comparing the compendial culture based method (membrane filtration) against three rapid methods. The rapid methods evaluated where: Milliflex Detection System, BacT/Alert and BACTEC.

In short these methods function by:

BACTEC: early detection of bacterial growth based on CO2 fluorimetric detection
BacT/Alert: detection of bacterial growth based on CO2 colorimetric detection
Rapid Milliflex: photons generated ATP bioluminescence are captured and detected

The research findings to date are that the compendial method, Rapid Milliflex, BacT/Alert, and BACTEC each showed equivalent sensitivity at detection of lowest spiked microorganism level.

Of the rapid methods, the researchers state that the: “Milliflex Detection System appears to be a promising alternative to the compendial sterility test for filterable biological products”.

The poster can be viewed at http://www.fda.gov/downloads/BiologicsBloodVaccines/ScienceResearch/UCM266975.pdf

FDA LAL

The status of the FDA LAL Guidance (written in 1987 and revised in 1991) is that, as has been confirmed that the FDA (in July 2011), that the guidance has been withdrawn. In its place, the FDA regard the USP Bacterial Endotoxin Test chapter <85> in the United States Pharmacopoeia as the 'definitive' guide to LAL testing.

It is acknowledged that, although useful, the USP chapter leaves some areas of LAL testing which are not adequately covered or explained. There is certainly the need for a new guideline.

To see the FDA link http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124785.htm#8.

Posted by: Dr. Tim Sandle

Developments in Regulatory Requirements Part 2

timsandle@btinternet.com (Tim Sandle) — Tue, 07 Feb 2012 06:00:19 PST

Developments in Regulatory Requirements Part 2

By Tim Sandle

This post follows on from Part 1, which looked at changed to the United States Pharmacopoeia. This post examines the European Pharmacopoeia.

The European Pharmacopoeia is revised and issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM). The EDQM (Council of Europe) is a key European Organisation involved in Harmonisation & Co-ordination of Standardisation, Regulation & Quality Control of Medicines, Blood Transfusion, Organ Transplantation, Pharmaceuticals and Pharmaceutical Care. The European Pharmacopoeia was first published in 1967.

The European Pharmacopoeia is published in two volumes. The first volume consists of general chapters (such as the sterility test) and the second of specific monographs for materials (such as sodium heparin). All producers of medicines or substances for pharmaceutical use must apply the quality standards of the European Pharmacopoeia for the marketing and use of these products in Europe.

The 7^th edition of the European Pharmacopoeia was published in January 2011. Since then there have been a series of updates, issued via supplements.

Proposed changes:

2.6.31. Microbiological examination of herbal medicinal products for oral use - under revision

The European Pharmacopoeia is revising the following microbiology chapter: 2.6.31 Microbiological examination of herbal medicinal products for oral use.

The changes are designed to bring the chapter in close alignment to chapter 2.6.13, specifically:

The absence test for E. coli and the semi-quantitative test for bile-tolerant gram-negative bacteria (probable number method) to become same methods as those currently published in the harmonised chapter 2.6.13.
The proposed method for Salmonella (test for absence) is similar to the method currently published in chapter 2.6.13 but the proposed method was adapted to the increased sample size (25 g or 25 ml instead of 10 g or 10 ml), shown to be appropriate for herbal medicinal products.
For herbal medicinal products with naturally high bioburden the use of buffered peptone medium instead of casein soya bean digest broth is proposed because of higher buffer capacity.

A separate chapter is still required because herbal drugs are outside the scope of pharmacopoeial harmonisation.

Recent changes:

European Pharmacopoeia: Rapid implementation of revised general chapter 5.2.8

An important European Pharmacopeia update was the rapid implementation of revised general chapter 5.2.8. The revised general chapter 5.2.8 “Minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products” was been adopted following a fast-track procedure and is to be implemented on 1 July 2011.

Transmissible Spongiform Encephalopathies (TSEs) are chronic degenerative nervous diseases characterised by the accumulation of an abnormal isoform of a cellular glycoprotein (known as PrP or prion protein).

The chapter focuses on:

Control measures
Selection of starting materials
Design and control of manufacturing

When manufacturers have a choice the use of materials from ‘non TSE-relevant animal species’ or non-animal origin is preferred.

Posted by: Dr. Tim Sandle

Contaminated watermelons cause salmonella outbreak in UK

timsandle@btinternet.com (Tim Sandle) — Mon, 06 Feb 2012 08:30:02 PST

An outbreak of salmonella has occurred in the UK, infecting 35 people. The cause has been traced to watermelons.

Avhigh number of infections caused from a Salmonella bacterium have been detected across the east of England. In total 35 people have become infected and one person has died as a result of bacterial toxin.

The cases of infection began in December and reached a high-point towards the end of January. Genetic level testing, co-ordinated by the UK Health Protection Agency (HPA), has revealed that the strain causing the infections is the same as a strain detected in Ireland and Germany. The strain of salmonella is called Salmonella newport.

Further testing has linked the bacterial infection to a batch of watermelons. The contamination is likely to have been on the outside of the melons and transferred when the melons were cut. The outside of the melons probably became contaminated from unclean water, which may have been used to wash or to store the fruit.

To read more, see the Digital Journal.

Posted by: Dr. Tim Sandle

Developments in Regulatory Requirements Part 1

timsandle@btinternet.com (Tim Sandle) — Mon, 06 Feb 2012 06:00:05 PST

Developments in Regulatory Requirements Part 1

By Tim Sandle

This series surveys some of the recent developments in Regulatory Requirements. It follows on from a paper delivered at the 2010 Pharmig conference which reviewed regulatory developments between 2009 and 2010 (if you would like a copy of this, please drop me an email).

The regulatory developments documented have been drawn from a review of documents and statements issued by regulators and standards organisations. The information has been highlighted and reviewed on the pharmaceuticalmicrobiology web log.

By ‘regulatory developments’ I am referring to pharmacopoeial changes, inspectorate guidelines (EMA and FDA) and documents issued by influential organisations like the World Health Organisation. The review of regulatory changes is divided into different sections, depending upon the body which issued the change or proposed change.

a) United States Pharmacopoeia

The United States Pharmacopoeia (USP) is the official pharmacopoeia of the United States, published dually with the National Formulary as the USP-NF. An edition of the USP is published each year.

According to Sutton and Tirumalai (2011)[1]:

“USP includes two distinct types of chapters: standards and informational documents. USP standards, microbiological methods included, are referee tests that have a scientific as well as a legal standing—they are expert standards, not consensus standards. Second, they are not intended to be batch release methods. They are standards that describe minimal expectations for the quality of medicinal products. If, for example, a pharmaceutical product does not fulfill the requirements of the appropriate USP monograph, then it is “mislabeled” or “adulterated,” based on the provisions of the Federal Food, Drug, and Cosmetic Act, and the Food and Drug Administration (FDA) can take enforcement actions.”

A list of microbiological chapters in the USP is included as an appendix to this report.

Pharmacopoeial Forum (PF) is the journal through which USP develops and revises USP–NF standards by a process of public review and comment. All changes and additions to the USP–NF are first proposed in the PF to invite public comment.

Proposed changes

Revision of USP Chapter 1116

In the Pharmacopeial Forum 36, number 6, the USP published the proposal of a complete revised version of chapter <1116> “Microbiological Evaluation of Clean Rooms and Other Controlled Environments". The proposed revision includes a change of the title to "Microbiological Control and Monitoring of Aseptic processing Environments".

This chapter of the USP provides guidance for microbiological evaluation for clean rooms, restricted access barrier systems (RABS) and isolators used for aseptic processing. The chapter applies to facilities which require levels of contamination control for aseptically produced sterile products.

The proposed revisions include:

· The change of the clean room classification standards from Federal Standard 209E to ISO 14644 in subchapter "Clean Room Classification for Aseptic Environments" (this ends the practices of using the outdated Mx standards).

· In addition developments in advanced aseptic technologies are mentioned, such as isolators and restricted access barrier systems (RABS).

· This proposed revision introduced a new measure, incidence frequency. One method of dealing with uncertain quantitative data is to treat it as qualitative data. In this approach, analysts recognize that 2 CFU is not materially different from 7 CFU on a plate, but the fact that there are colonies on the plate at all is the key fact. In effect, analysts are counting non-zero events.

Revision of USP chapter <1113> "Microbial Identification"

USP chapter <1113> "Microbial Identification" is currently under revision (Pharmacopeial Forum 36 number 6). The chapter title is proposed to change to: "Microbial Characterization, Identification and Strain Typing".

The aim of the chapter is to address methods of microbial identification. The revision is designed to bring the chapter up-to-date with current microbial characterization methods. The chapter will thus include sections on phenotypic and genotypic methods for identification.

The chapter also contains information relating to:

Reference to phenotypic and genotypic methods (without listing any specific suppliers)
The verification of different identification methods.
Procedures for the isolation of pure cultures of stressed micro organisms.
The importance of microbial characterisation for many risk assessments.
The importance of strain level identification to determine the source of a microorganism as part of out of specification investigations.

Revision of Verification of Compendial Methods

General Chapter <1226> Verification of Compendial Methods is under revision (Pharmacopeial Forum November/December 2010). The update aims proposes a change in the section marked "Verification Process", where the following paragraphs have been added:

"The verification process for compendial test procedures is the assessment of whether the procedure can be used for its intended purpose, under the actual conditions of use for a specified drug substance and/or drug product matrix."

"The process of assessing the suitability of a compendial analytical test procedure under the conditions of actual use may or may not require actual laboratory performance of each analytical performance characteristic."

It is proposed that the following points are added to the list of items to be considered for the Verification of Compendial Procedures:

• Drug substance's synthetic route

• Method of manufacture for the drug product

• Effect of the matrix on the recovery of impurities

• Suitability of chromatographic conditions and column

• Appropriateness of detector signal response

Revision to <85> Bacterial Endotoxins Tests

The chapter is likely to be revised because:

a) From a clinical perspective, commonly accepted endotoxin limits may in fact be too high.

b) Advances in technology, such a recombinant products based on a recombinant Factor C.

c) Advances in technology based on highly automated endotoxin test kits.

Proposed new chapter <63> Mycoplasma Tests

This new chapter proposal contained methods to detect Mycoplasma contamination of test articles, tissues and/or cell cultures used to produce test articles, or any other material in which Mycoplasma contamination was suspected.

Test methods either: cultural methods, nucleic acid amplification techniques, enzymatic activity–based method, or other similar tests.

Proposed new chapter <610> Alternative Microbiological Sampling Methods for Nonsterile Inhaled and Nasal Products

The aim is set out the basis for special approaches for sampling of either low-or high-content inhaled or nasal dosage forms, to encourage methodologies that employ aseptic techniques and are conducted under environmental and other conditions that are appropriate for aseptic sampling.

Proposed new chapter: <1224> Transfer Of Analytical Procedures (NEW)

This proposed new General Information chapter (revision proposal target USP35-NF30), is part of a series of General Chapters that provide guidance for generation of data in support of compendial analytical procedures.

Changes to Sterilisation

USP chapter <1211> “Sterilization and Sterility Assurance of Compendial Articles” is being revised. The chapter will change its focus and consider general concepts for sterility assurance only (the goal being sterilisation at a more basic level with more instruction and with less standardisation). The changes will include removal of any description of the sterility test (instead UPS <71> will be referred to). There will also be some tidying up of the chapter, such as the removal of out dated irradiation sterilisation references.

With USP <1211> slimmed down a new chapter: <1229> is proposed. This chapter will be entitled “General Concepts for Sterilization”. The chapter will consist of a series of sub-chapters. Each sub-chapter will cover an important sterilisation method:

Chemical Sterilization – (includes aldehydes, oxidizers, halides, acids, bases)
Dry Heat Depyrogenation (using endotoxin indicators)
Sterilization by Filtration – heavily revised
Gas Sterilization (includes ETO, chlorine dioxide, ozone)
Dry Heat Sterilization (using the biological indicator B. atrophaeus)
Steam Sterilization of Liquids
Radiation Sterilization
Steam Sterilization of Parts
Vapor Sterilization – (includes H₂O₂, and peracetic acid)

Revision to <1231> Water for Pharmaceutical Purposes

The revision was indicated in the Pharmacopeial Forum May / June 2011, with an implementation target for the USP35-NF30 1st Supplement.

A number of changes are proposed for this general information chapter related to packaged waters and how leachable organics from the packaging components render the waters sometimes significantly less pure. The changes are:

Microbial control of nonsterile waters
Risk of leachables frompackaging that may render them unsuitable for certain uses. Additional discussion of packaging leachables has been added to the section on Sterile Water for Injection, as well as to the Chemical Considerations section regarding how the original organic purity test, Oxidizable substances, facilitated the presence of organic packaging leachables, particularly in the sterilized waters.
Additional changes are proposed to the discussion of Pure Steam to clarify the lack of need for microbial testing, and to the discussion of Filtered Water and High-Purity Water to correct inaccuracies.

Recent changes

These recent changes relate to the update to United States Pharmacopoeia (USP34 NF29) (official from 1st May 2011). The main changes are:

i) Monograph: Water for Injection

The monograph was revised to reference both bulk and packaged forms and under specific tests:

Water Conductivity
The addition of ‘Bulk Water’ Bacterial Endotoxins Test, limit changed to read ‘Less than’ (changed from “it contains less than”)
Additional Requirements, Packaging and Storage, Labelling are added.

[1] Sutton, S. and Tirumalai, R. (2011). “Activities of the USP Microbiology and Sterility Assurance Expert Committee During the 2005–2010 Revision Cycle”, American Pharmaceutical Review, July / August 2011, pp13-30Posted by: Dr. Tim Sandle

Dry ice blasting in pharmaceutical manufacturing

timsandle@btinternet.com (Tim Sandle) — Sun, 05 Feb 2012 04:00:01 PST

An interesting new technology is emerging in pharmaceutical manufacturing: dry ice blasting within cleanrooms.

Pharmaceutical manufacturing cleanrooms and clean chambers need to meet cleanliness classifications as prescribed by the FDA, EU GMP and in ISO 14644. This is achieved through regular cleaning and validation.
Typically, the cleaning involves manual scrubbing and disinfecting with various solutions and chemicals, following which the entire room and equipment must be dried thoroughly tested.

One alternative method is dry ice blasting.

Dry ice blasting offers several advantages in these environments including absence of chemicals in the cleaning process in addition to being a completely dry process that does not damage equipment or introduce any liquid into the cleanroom.

Additionally, dry ice cleaning has been proven to clean at the molecular level, saving considerable time and money in pharmaceutical manufacturing applications.

Dry ice blasting is an excellent process to clean containers, tanks, drums, capsule manufacturing and tablet pressing machines, emulsifiers and tablet coaters, reactors, homogenisers, agitators and mixers, separators, granulators and drying equipment as well as conveyors and packaging machinery among others.

Does any one have experience of this technology or its intended application?

Posted by: Dr. Tim Sandle

Can intestinal bacteria can influence mood?

timsandle@btinternet.com (Tim Sandle) — Sat, 04 Feb 2012 05:02:49 PST

"An extraordinary profusion of microscopic critters inhabit every crack and crevice of the typical human, so many that they probably outnumber the cells of the body upon and within which they dwell." So says a review of some latest scientific research. Headline grabbing? Maybe. Here is the report, taken from the general media.

From The Economist -

These microbes are mostly harmless. Some of them, particularly those that live in the gut, are positively beneficial, helping with digestion and keeping the intestines in good working order. That is no surprise—bacteria as much as people have an interest in keeping their homes in sound condition. What is surprising is the small but growing body of evidence which suggests that bacteria dwelling in the gut can affect the brain, too, and thereby influence an individual’s mood and behaviour. The most recent paper on the topic, published this week in the Proceedings of the National Academy of Sciences, reports (like much of the research in this field) on results in mice.

The researchers, led by Javier Bravo of University College, Cork, split their rodent subjects into two groups. One lot were fed a special broth containing Lactobacillus rhamnosus, a gut-dwelling bacterium often found in yogurt and other dairy products. The others were fed an ordinary diet, not fortified with microbes.

The team then subjected the mice to a battery of tests that are used routinely to measure the emotional states of rodents. Most (though not all) of these tests showed significant differences between the two groups of animals.

One test featured a maze that had both enclosed and open tunnels. The researchers found that the bacterially boosted mice ventured out into the open twice as often as the control mice, which they interpreted to mean that these rodents were more confident and less anxious than those not fed Lactobacillus.

In another test the animals were made to swim in a container from which they could not escape. Bacteria-fed mice attempted to swim for longer than the others before they gave up and had to be rescued. Such persistence is usually interpreted by students of rodent behaviour as evidence of a more positive mood.

Direct measurements of the animals’ brains supported the behavioural results. Levels of corticosterone, a stress hormone, were markedly lower in the bacteria-fed mice than they were in the control group when both groups were exposed to stressful situations. The number of receptors for gamma-aminobutyric acid, a natural chemical messenger that helps dampen the activity of certain nerve cells, varied in statistically significant ways between the brains of the two groups, with more in some parts of the treated animals’ brains and fewer in others. Most intriguing of all, when Dr Bravo cut the animals’ vagus nerves—which transmit signals between the gut and the brain—the differences between the groups vanished.

The idea that gut-dwelling microbes can affect an animal’s state of mind may strike some people as outlandish, and there are certainly loose ends still to be tied up. Beyond their evidence that the vagus nerve is crucial to the relationship, for example, Dr Bravo and his colleagues do not yet know the precise mechanisms at work. There is also an obvious follow-up question: whether a similar thing is going on in people. A few previous studies have hinted at the possibility. For example, bacterial treatments may help with the mental symptoms of illnesses such as irritable-bowel syndrome.

All this is forcing a reassessment of people’s relationship with the bacteria that live on and in them, which have long been regarded mainly as a potential source of infections. An editorial in this week’s Nature raises the possibility that the widespread prescription of antibiotics—which kill useful bacteria as effectively as hostile ones—might be one factor behind rising rates of asthma, diabetes and irritable-bowel syndrome. If Dr Bravo’s results apply to people, too, then mood disorders may end up being added to this list.

Posted by: Dr. Tim Sandle

European Medicines Agency and European Food Safety Authority commit to greater co-operation

timsandle@btinternet.com (Tim Sandle) — Fri, 03 Feb 2012 12:37:09 PST

In a statement from the EMA:

The European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) havesigned a memorandum of understanding setting out their commitment to fostering co-operation on areas of common interest.

The new agreement builds on the existing collaboration between the agencies, setting out a number of activities to ensure that they make best use of their resources while avoiding duplication of effort. These include developing the scientific excellence of the two agencies and optimising risk assessment activities across the European Union (EU).

For details, see the EMA.

Posted by: Dr. Tim Sandle

PDA's 7th Annual Global Conference on Pharmaceutical Microbiology

timsandle@btinternet.com (Tim Sandle) — Fri, 03 Feb 2012 06:00:00 PST

Date: 22nd - 24th October, 2012

Location: Bethesda, USA

Summary:
Pharmaceutical - Conference, Exhibition

PDA's 7th Annual Global Conference on Pharmaceutical Microbiology will bring together all levels of industry professionals to network and benefit from a program that reveals the essential science of microbiology and seeks to solve the problems that our industry faces on a daily basis. The comprehensive program agenda will include presentations from regulatory and industry representatives from around the world who will share recent case studies, current and future trends in the field of pharmaceutical microbiology.

For more details: PDA Microbiology

Posted by: Dr. Tim Sandle

Dr Rosemary Simpson

timsandle@btinternet.com (Tim Sandle) — Thu, 02 Feb 2012 15:35:26 PST

It is with great sadness that this blog reports on of the death of Dr Rosemary Simpson.

Dr Simpson was involved in a traffic accident some days ago and never regained consciousness.

Dr Simpson was an active member of the decontamination community. She was a member of many International standards bodies and was chairperson of BSI LBI/35 dealing with sterilizer and washer disinfector equipment. Along with Prof David Hurrell, Dr Simpson was a co founder of Health Care Sciences.
Posted by: Dr. Tim Sandle

Pharmig News #46 published

timsandle@btinternet.com (Tim Sandle) — Thu, 02 Feb 2012 14:51:00 PST

The new edition of the Pharmaceutical Microbiology Interest Group (Pharmig) Newsletter has been published (issue #46).

In the issue is:

Latest industry news by Tony Mayhall
An article about control charting by Tim Sandle and Jennifer Sandle
A review of the latest books for microbiologists
A review of Pharmig’s 19th annual conference, by Susan Birks of Manufacturing Chemist and Cleanroom Technology
The latest pharmaceutical and healthcare news

The newsletter is sent out to all member sites. To purchase an individual copy, contact the Pharmig office.

For those interested in my writing, the reference for the control charting article is:

Sandle, T. and Sandle, J. (2012). “Data Analysis – Shewhart Chart”, Pharmig News, Number 46, pp2-5

Posted by: Dr. Tim Sandle

Antibiotic Action

timsandle@btinternet.com (Tim Sandle) — Thu, 02 Feb 2012 06:30:00 PST

The British Society for Antimicrobial Chemotherapy has launched the campaign group Antibiotic Action to call for greater investment and interest in this area.

Antibiotic Action is a global initiative established by the British Society for Antimicrobial Chemotherapy (BSAC). The group hasserious concerns regarding the future effectiveness of currently available antibiotics and the lack of antibiotic agents in the drug pipeline. Antibiotic Action is a forum which calls upon all parties – government, health professionals, industry and charities – to identify and implement solutions within the research, regulation and economic markets to stimulate and regenerate interest in the discovery and development of antibiotic agents of the future.

For more details: Antibiotic Action
Posted by: Dr. Tim Sandle

Anti-infective drug shortages pose 'health threat'

timsandle@btinternet.com (Tim Sandle) — Wed, 01 Feb 2012 08:30:00 PST

A review in Clinical Infectious Diseases has indicated that shortages of key drugs used to fight infections represents a public health emergency in the USA, and could lead to patient's lives being put at risk. The review was undertaken by Marc Scheetz and Milena Griffith from Midwestern University Chicago College of Pharmacy and Northwestern Memorial Hospital.

The reasons for this relate to shortages of anti-infective drugs, a slowdown in the development of new anti-infective drugs and the increase of multi-drug resistant pathogens. In the report, the authors point to several supply-side issues which may account for supply issues. These include problems with procuring raw materials, processing, distributing, regulatory compliance, market shortages due to epidemics, new therapeutic indications, and perceived shortages.

The abstract to the study (Clin Infect Dis. (2012) doi: 10.1093/cid/cir954) reads:

"Anti-infective shortages pose significant logistical and clinical challenges to hospitals and may be considered a public health emergency. Anti-infectives often represent irreplaceable life-saving treatments. Furthermore, few new agents are available to treat increasingly prevalent multidrug-resistant pathogens. Frequent anti-infective shortages have substantially altered patient care and may lead to inferior patient outcomes. Because many of the shortages stem from problems with manufacturing and distribution, federal legislation has been introduced but not yet enacted to provide oversight for the adequate supply of critical medications. At the local level, hospitals should develop strategies to anticipate the impact and extent of shortages, to identify therapeutic alternatives, and to mitigate potential adverse outcomes. Here we describe the scope of recent anti-infective shortages in the United States and explore the reasons for inadequate drug supply."

For more about this issue, see Modern Medicine.

Main sources of food poisioning

timsandle@btinternet.com (Tim Sandle) — Wed, 01 Feb 2012 06:00:01 PST

Over 90% of cases of a common form of food poisoning seen this year were due to people eating undercooked chicken liver pate, often at weddings.

This is according to a news report by the BBC and based on an analysis by the Health Protection Agency (HPA), who analysed 18 outbreaks of Campylobacter in 2011 across England.

In all, 443 people became unwell and one had to be hospitalised.

The Food Standards Agency (FSA) has reminded caterers to cook poultry livers to prevent infection.

Campylobacter is the most common cause of bacterial food poisoning in Britain - there were estimated to have been more than 600,000 cases in 2010 in England and Wales.

Symptoms include diarrhoea, stomach pains and cramps, fever, and generally feeling unwell. Most people are only ill for a few days.

In 2008 there were just three outbreaks linked to undercooked chicken liver pate, but that rose to nine in 2009 and 14 in 2010.

Poultry livers carry a particularly high risk of Campylobacter as the bacteria can be present throughout the liver, not just the surface as is the case for other poultry meat, and may remain a source of infection if they are not cooked sufficiently.

Of the 18 outbreaks, 14 occurred in catering venues, and 13 of these were linked to chicken or duck liver pate.

Seven were linked to wedding receptions at hotels, banqueting venues or public houses and six were associated with catering at other functions such as hotels, clubs and restaurants.

The HPA found that livers used to make the parfait or pate were undercooked allowing the liver to remain pink in the centre.

It said caterers can reduce the risk of their people becoming infected by ensuring that Campylobacter is killed through proper cooking and by avoiding cross-contamination to other foods.'Inadequate cooking'

Dr Christine Little, an expert in gastrointestinal infections at the HPA, said: "The increase in outbreaks which are due to the consumption of chicken liver pate has been steadily increasing over the last few years.

"Not only is this dish popular in food recipe magazines, it is being served in a variety of different catering venues.

"Illness occurs because the livers are only cooked until they are pink, and inadequate cooking will not be sufficient to kill the bacteria.

"Both the public and the catering industry need to be aware that undercooking this product can result in food poisoning."

She said anyone planning a wedding, or other special event, should be aware of the risks if they were having chicken liver pate to prevent people becoming unwell.

The FSA issued updated advice to caterers on the safe handling and cooking of livers twice in 2010, but Campylobacter outbreaks associated with the consumption of chicken liver pate have continued to occur.

Bob Martin, head of foodborne disease strategy at the FSA, said: "Unfortunately, levels of Campylobacter in most raw chicken are high, so it's really important that chefs cook livers thoroughly to kill any bacteria, even if recipes call for them to be seared and left pink in the middle.

"The only way of ensuring the pate or parfait will be safe to serve to your guests or customers is by cooking the livers the whole way through.

"Caterers should also follow good general hygiene practices when cooking and handling poultry livers, to avoid cross contamination with Campylobacter."

Posted by: Dr. Tim Sandle

Hot microbiology and pharma topics!

timsandle@btinternet.com (Tim Sandle) — Tue, 31 Jan 2012 08:00:05 PST

Listed below are the mist popular microbiology, quality assurance, pharmaceutical and healthcare related items on this blog during the past month. Please have a look through, they will probably be something of interest.

If you have any suggestions for news items or comments on this site - pharmaceutical microbiology - please contact me.

Advances in cleanroom technologies

The gorgeous molecular biology movie

UK bacteraemia reports

Quality Management #1: Quality Management Systems

Laboratory data tables

Quality Control Laboratories: An Inspector's Guide

Air Quality and Cleanrooms (free on-line paper)

Bacillus anthracis and Anthrax: history

Evaluation of contact plates for environmental monitoring

Posted by: Dr. Tim Sandle

Quality Risk Management documents

timsandle@btinternet.com (Tim Sandle) — Tue, 31 Jan 2012 11:57:47 PST

A blog reader has asked me for a list of documents pertaining to Quality Risk Management. Quality Risk Management allows process and products, and in some cases personnel, to be better protected and it can be used to help to meet regulatory expectations and to meet cost demands or to seek process efficiency.

Here are the key ones (together with some relevant links):

Posted by: Dr. Tim Sandle

Choosing Cleanroom Clothing

timsandle@btinternet.com (Tim Sandle) — Mon, 30 Jan 2012 06:30:00 PST

Cleanroom clothing is an important part of contamination control, particularly in preventing operators from shedding skin (and thereby microorganisms).

Pharmaceutical Technology Europe have an interesting interview with Jaime Cassar, cleanroom category manager at Kimberly-Clark Professional Europe, about the importance of sterile garments for cleanroom environments.

Here is an extract:

How can the protection provided by sterile clothing help to create process improvements?

The cleanliness of sterile clothing is important to consider in order to prevent the clothing from itself becoming a source of contamination. For example, sterile gloves that have been washed in di-ionised water, cleanroom packed, sterile validated and specified for low endotoxin levels can help lower the risk of particle, microbiological and endotoxin contamination. Sterile apparel that is laundered, cleanroom packed in individual vacuum packaging, double-bagged and provided with periodic sterile validation will also contribute to lower contamination risks. Sterile gloves made from synthetic materials are beneficial because they can eliminate the risk of contaminating the final product with rubber latex proteins, which can be a problem for patients with latex allergies.

Another crucial point is the barrier performance of the clothing. Continuous improvement can come from better control or elimination of variability in attributes that impact barrier performance. For example, disposable apparel eliminates the risk of variability in filtration efficiency and material strength that may come from re-wearing, re-washing and re-sterilising apparel many times and over a long period of time. Sterile apparel made from stronger materials and sterile gloves with a higher quality film formation will be more resistant to breakage and are more likely to be free from any pinhole type defects.

As well as protecting the process from contamination, sterile clothing should also protect the wearer from the health and safety risks presented by chemicals and APIs. Sterile gloves tested to show longer resistance times to permeation by cytotoxic chemicals and sterile clothing certified to provide protection against chemical splashes can contribute to better protection for the wearer. In Europe, sterile gloves and apparel should be Category III certified under the personal protective equipment (PPE) directive 89/686/EEC, if there is risk of exposure to chemicals and APIs. There are also other ways to protect wearers from health and safety risks. For example, sterile clothing that is biocompatible can mitigate the risk of the clothing causing irritation to the wearer, and sterile gloves that are free from natural rubber latex will eliminate the risk of latex allergies.

Posted by: Dr. Tim Sandle

Sustainable water-treatment process using tree seeds

timsandle@btinternet.com (Tim Sandle) — Sun, 29 Jan 2012 15:18:51 PST

A material derived from seeds of a tree, sometimes called the "miracle tree", could purify and clarify water inexpensively and sustainably in the developing world, where many millions of people lack access to clean drinking water. Research, led by Stephanie Velegol, on the potential of a sustainable water-treatment process requiring only tree seeds and sand has been reported in the journal Langmuir.

Velegol looked to Moringa oleifera, also called the "miracle tree," a plant grown in equatorial regions for food, traditional medicine and biofuel. Past research showed that a protein in Moringa seeds can clean water, but using the approach was too expensive and complicated. So Velegol's team sought to develop a simpler and less expensive method.

To achieve this, the researchers added an extract of the seed containing the positively charged Moringa protein, which binds to sediment and kills many microorganisms, to negatively charged sand. The resulting "functionalized," or "f-sand," proved effective in killing harmful E. coli bacteria and removing sediment from water samples. The results could lead to applications using f-sand to provide a simple, locally sustainable process for producing storable drinking water.

The moringa tree is grown mainly in semi-arid, tropical, and subtropical areas, corresponding in the United States to USDA hardiness zones 9 and 10. While it grows best in dry sandy soil, it tolerates poor soil, including coastal areas. It is a fast-growing, drought-resistant tree that is native to the southern foothills of the Himalayas in northwestern India.

The journal reference is: Huda A. Jerri, Kristin J. Adolfsen, Lauren R. McCullough, Darrell Velegol, Stephanie B. Velegol. Antimicrobial Sand via Adsorption of Cationic Moringa oleifera Protein. Langmuir, 2011
Posted by: Dr. Tim Sandle

Cleanroom cleanliness classes

timsandle@btinternet.com (Tim Sandle) — Sat, 28 Jan 2012 18:30:00 PST

Here is a table showing the comparison between EU GMP cleanroom grades and ISO 14644 cleanroom classes.

	At Rest
	0.5 µm				5.0 µm
Grade	Annex 1		ISO 14644-1 (Class) Count		Annex 1		ISO 14644-1 (Class) Count
A	3,520		(5) 3,520		20		(4.8) 20
B	3,520		(5) 3,520		29		(5) 29
C	352,000		(7) 352,000		2,900		(7) 2,930
D	3,520,00		(8) 3,520,000		29,000		(8) 29, 300
		Operational
		0.5 µm				5.0 µm
Grade		Annex 1		ISO 14644-1 (Class) Count		Annex 1		ISO 14644-1 (Class) Count
A		3,520		(5) 3,520		20		(4.8) 20
B		352,000		(7) 352,000		2,900		(7) 2,930
C		3,520,000		(8) 3,520,000		29,000		(8) 29,300
D		Not Defined				Not Defined

Posted by: Dr. Tim Sandle

Can intestinal bacteria influence mood?

timsandle@btinternet.com (Tim Sandle) — Sat, 28 Jan 2012 06:27:35 PST

Many of the bacteria which reside in the human gut, are beneficial, helping people with digestion and keeping the intestines in good working order. This is fairly well established in scientific research.

From this starting point, there is a small, but steadily growing, body of evidence which suggests that bacteria dwelling in the gut can affect the brain, too, and thereby influence an individual’s mood and behaviour. A recent paper on the topic was recently published in the Proceedings of the National Academy of Sciences. The study reports on results in mice.

The researchers, led by Javier Bravo of University College, Cork, split their rodent subjects into two groups. One lot were fed a special broth containing Lactobacillus rhamnosus, a gut-dwelling bacterium often found in yogurt and other dairy products. The others were fed an ordinary diet, not fortified with microbes.

The team then subjected the mice to a battery of tests that are used routinely to measure the emotional states of rodents. Most (though not all) of these tests showed significant differences between the two groups of animals.

One test featured a maze that had both enclosed and open tunnels. The researchers found that the bacterially boosted mice ventured out into the open twice as often as the control mice, which they interpreted to mean that these rodents were more confident and less anxious than those not fed Lactobacillus.

In another test the animals were made to swim in a container from which they could not escape. Bacteria-fed mice attempted to swim for longer than the others before they gave up and had to be rescued. Such persistence is usually interpreted by students of rodent behaviour as evidence of a more positive mood.

Direct measurements of the animals’ brains supported the behavioural results. Levels of corticosterone, a stress hormone, were markedly lower in the bacteria-fed mice than they were in the control group when both groups were exposed to stressful situations. The number of receptors for gamma-aminobutyric acid, a natural chemical messenger that helps dampen the activity of certain nerve cells, varied in statistically significant ways between the brains of the two groups, with more in some parts of the treated animals’ brains and fewer in others. Most intriguing of all, when Dr Bravo cut the animals’ vagus nerves—which transmit signals between the gut and the brain—the differences between the groups vanished.

Some doubts, however, remain. Dr Bravo and his colleagues do not yet know the precise mechanisms at work. The key question which emerges from the research is whether a similar effect occurs in people. Studies which use bacterial treatments to help with mental symptoms of illnesses such as irritable-bowel syndrome would suggest so.

All this is forcing a reassessment of people’s relationship with the bacteria that live on and in them, which have long been regarded mainly as a potential source of infections.

Reference: Bravo, Forsythe, Chew, Escaravage, Savignac, Dinan, Bienenstock & Cryan. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS http://dx.doi.org/10.1073/pnas.1102999108

For further information: University of Cork

Posted by: Dr. Tim Sandle

Hepatitis drug developments

timsandle@btinternet.com (Tim Sandle) — Sat, 28 Jan 2012 01:55:37 PST

Two new drugs have recently been approved to help those suffering from the virus hepatitis C. The FDA have approved Incivek (telaprevir) from Vertex Pharmaceuticals and Merck’s Victrelis (boceprevir). Both pills are protease inhibitors that interfere with the liver-infecting virus's ability to replicate, and each drug can be combined with existing treatment to make the life of the patient easier and closer to 'normal'. The development was reported in The New York Times.

Further in relation to hepatitis treatment, the pharmaceutical company Gilead recently purchased the biotech company Pharmasset and its hepatitis C development program for $11 billion. Also on the subject of acquisitions, Johnson & Johnson and Bristol-Myers Squibb are jointly working on a hepatitis C drug combination, which is set to begin Phase III clinical trials in 2012

Read more: see a special report on the Digital Journal site

Posted by: Dr. Tim Sandle

WHO HVAC Document (revised edition)

timsandle@btinternet.com (Tim Sandle) — Sat, 04 Feb 2012 10:44:25 PST

The World Health Organization has revised their guidance on Heating Ventilation and Air Conditioning (HVAC) systems. This forms part of Technical Report 961, as Annex 5.

The document covers the following topics: products and personnel, air filtration, unidirectional airflow, infiltration, cross-contamination, displacement concept (low pressure differential, high airflow), pressure differential concept (high pressure differential, low airflow), physical barrier concept, temperature and relative humidity, protection of the environment, design of HVAC systems and components and commissioning, qualification and maintenance.

The introduction to the document reads:

“This document aims to give guidance to pharmaceutical manufacturers and inspectors of pharmaceutical manufacturing facilities on the design, installation, qualification and maintenance of the HVAC systems. These guidelines are intended to complement those provided in Good manufacturing practices for pharmaceutical products and should be read in conjunction with the parent guide. The additional standards addressed by the present guidelines should, therefore, be considered supplementary to the general requirements set out in the parent guide”

The document can be found at: WHO HVAC

Posted by: Dr. Tim Sandle

Links for 2011-12-30 [Digg]

Sat, 31 Dec 2011 00:00:00 PST

Cleanroom Standard ISO14644 Part 8
Latest on cleanroom standards Cleanroom Standard ISO14644 Part 8

Links for 2011-10-22 [Digg]

Sun, 23 Oct 2011 00:00:00 PDT

Pharmaceutical Microbiology: Microbiology Laboratory Training
Training program for a laboratory

Links for 2011-10-21 [Digg]

Sat, 22 Oct 2011 00:00:00 PDT

The 25 Highest-Paid Musicians In The World
U2, Bon Jovi, Elton John and Lady Gaga top Forbes' list of the Highest-Paid Musicians in the World.

Links for 2011-09-23 [Digg]

Sat, 24 Sep 2011 00:00:00 PDT

Pharmaceutical Microbiology: Gram stain method (illustrated)
Step-by-step guide to bacterial staining

Links for 2011-09-18 [Digg]

Mon, 19 Sep 2011 00:00:00 PDT

cleanroom construction
Take a look at this excellent article on how to contruct a room, you will not be dissatisfied

Links for 2011-09-08 [Digg]

Fri, 09 Sep 2011 00:00:00 PDT

Two Extremes? Flexible Working in Europe by Tim Sandle - Lovereading UK
Two Extremes? Flexible Working in Europe by Tim Sandle - Lovereading UK.
Importance of Hand Santisation By Tim Sandle ~ Daily Dose Of Entertainment, Movies, Celebs, Games,Mobiles, Politics, Events , News

Links for 2011-09-04 [Digg]

Mon, 05 Sep 2011 00:00:00 PDT

Pharmaceutical Microbiology: Is an edible vaccine in our near future?
Immunizations taken with food? Sounds more pleasant than a jab in the arm, but could it be a reality? Scientists in Australia are getting ever closer to this revolutionary method that could protect people from many common diseases without the trauma and at a fraction of the cost.
Darling: Brown in No 10 was chaos
Gordon Brown's final years leading the Labour government were permanently in "chaos and crisis", says former chancellor Alistair Darling in his memoirs.