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

What is Pharmacovigilance? An introduction

This is part of an occasional series of educational posts. This post looks as Pharmacovigilance, from an EU GMP perspective.

Pharmacovigilance

The legal framework for pharmacovigilance for medicinal products in the EU/EEA is set out in a number of Directives, which describe the obligations of Marketing Authorisation Holders and the Regulatory Authorities. This requires them to set up a system for pharmacovigilance in order to:

• Collect, collate and evaluate information about reported and suspected adverse reactions 
• Share relevant information to allow all parties involved to meet their obligations and discharge their responsibilities.

Information about drug safety is obtained from a number of sources including:

• Spontaneous adverse drug reaction (ADR) reporting schemes, for example, the UK’s “Yellow Card” Scheme. 
• Clinical studies and investigation of health and diseases in wider populations. 
• Information from pharmaceutical companies and information published in medical literature. 
• Information from regulatory authorities worldwide and from morbidity and mortality databases. 

Marketing authorisation holders are required to operate a system to monitor and report back to the authorities on the safety of their products. This requires the collection and reporting of spontaneous safety events and the collection and evaluation of safety data from various sources over the life of a medicine. For new products this is defined in a pharmacovigilance plan that is part of the risk planning information that accompanies an application for a marketing authorisation.

The MAH is required to have a documented system and the resources needed to meet these obligations and also to provide pharmacovigilance “Qualified Person” (which should not be confused with the Qualified Person responsible at a manufacturing site for batch certification).

The responsibilities of the DRAs of the EU Member States with regard to pharmacovigilance involve:

• The assessment of safety data and plans for marketed medicinal products. 
• The inspection of MAH pharmacovigilance systems. 
• The communication of safety information to stakeholders. 
• Taking necessary actions to prevent or mitigate safety problems (e.g. by the suspension of a marketing authorisation or by changes to therapeutic indications). 
• Entering safety information in a European Pharmacovigilance database (EudraVigilance). 

Further information can be found in either EudraLex Volume 9 at the reference given above. This contains guidelines for both human and veterinary pharmacovigilance.

Information on the MHRA’s Pharmacovigilance System can be found at: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=810

and

http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=827

Posted by Tim Sandle

Contamination control ‘under foot’

Contamination control within hospitals and pharmaceutical facilities is of great importance, either to protect patients from infection or protect products intended to be administered into patients from contamination. The primary contamination risk is from microorganisms – principally bacteria and fungi.

In relation to this area, Tim Sandle has written an article that assesses the types of contamination control systems for floors that are available to the medical and pharmaceutical sectors. This has been published in European Medical Hygiene.

The reference is:

Sandle, T. (2013). At Floor Level, European Medical Hygiene, Issue 4, pp26-31

For details about European Medical Hygiene see: EMH

Posted by Tim Sandle

Links to regulatory agencies

Some useful links to pharmacopoeia and regulators.

British Pharmacopoeia 
www.pharmacopoeia.org.uk

This link is directed to the homepage of the British Pharmacopoeia. Registered users can log onto the British Pharmacopoeia online. From this homepage information can also be found on how to register and how to order BP documents.

CFR Search
www.access.gpo.gov

This link allows a search for a Code of Federal Regulations (CFR). The Code of Federal Regulations (CFR) is a codification of the general and permanent rules published in the Federal Register by the Executive departments and agencies of the Federal Government. For example, 21 CFR Part 211 covers current Good Manufacturing Practice utilized in the pharmaceutical industry.


European Pharmacopoeia
www.pheur.org

This link is directed to the homepage of the European Pharmacopoeia. It provides information concerning EP news, activities, and upcoming European conferences. There are also downloadable catalogs listing publications and reference materials that may be ordered.


Food and Drug Administration
www.fda.gov

This link to the United States Food and Drug Administration provides information concerning FDA news, safety alerts, new product approvals, recalls, etc. The FDA’s pharmaceutical interests are divided into two sections: CDERoversees the research, development, manufacture and marketing of drugs while the CBER mission is to protect and enhance the public health through regulation of biological products including blood, vaccines, therapeutics and related drugs and devices. Access CDER’s Regulatory Guidance site or CBER’s Regulatory Guidance site to view and download specific documentation.

FDA's Industry Resource Center
www.fda.gov/oc/industry

This website provides direct links to: guidance documents, inspection references, information on imports, warning letters and other FDA enforcement activities. This site also provides easy access to the regulatory industry where companies can contact the FDA with questions, submit comments online about proposed FDA regulations and register to attend specific industry meetings.

Freedom of Information
www.fda.gov

This link is directed to the homepage of the Freedom of Information portion of the FDA website. It provides general information about FOI as well as Index search options and how to request information. Any information that is routinely available to the public and not found on the FDA's website may be requested. For instructions on how to submit a request for information, click on the following link: www.fda.gov. Visit the Index of Electronic Reading Room Documents to review the categories of frequently requested FDA documents and to view a list of specific FOI sites that have been established by various government agencies.

Warning Letter Search
www.fda.gov

This Web page is designed to simplify the search for Warning Letters, which are in PDF format. Browse Warning Letters using one of the following five categories: most recent, by company, by subject, by issuing office, by date; and search warning letters with search form.

GLP Regulations
www.mhra.gov.uk

This link is directed to the Good Laboratory Practice Regulation document in PDF format from the MHRA. It can be screen viewed or printed.


IEST (Institute of Environmental Sciences and Technology
www.iest.org

The Institute of Environmental Sciences and Technology, founded in 1953 as a not-for-profit association, is a multidisciplinary, international society whose members are internationally recognized for their contributions to the environmental sciences in the areas of contamination control, electronics manufacturing, and pharmaceutical processes. IEST is the Secretariat for ISO Technical Committee 209 charged with writing a series of international standards for clean rooms and associated controlled environments. ISO/DIS 14644-7 on Separative Enclosures can be ordered on the IEST web site.



JETT (Joint Equipment Transition Team)
www.jettconsortium.com

JETT is a consortium of pharmaceutical manufacturers, equipment suppliers, and consultants seeking to improve communications between Users and Suppliers to more effectively meet the "validation" requirements of the pharmaceutical industry. The goal of JETT is to provide a common technical language base, bid package formats, and validation test plan examples that follow GAMP guidelines and to promote communications between end users and vendors in the pharmaceutical industry. The site provides sample User Requirements Specification templates, including one on a production barrier isolator. You can also download publications that have been presented at recent pharmaceutical conferences.

Information Resources: MHRA Publications
www.mhra.gov.uk

This site lists the publications that are available and details on how to obtain them. Clicking on Inspection and Enforcement Publications will access the Guide to UK GLP Regulations 1999.



Medicines and Healthcare Products Regulatory Agency (UK)
www.mhra.gov.uk

This link is directed to the homepage of the United Kingdom's Medicines Control Agency. It provides general information as well as MCA news and current events.



Pharmaceutical Inspection Convention
www.picscheme.org

PIC (Pharmaceutical Inspection Convention) was founded in October 1970 by EFTA (European Free Trade Association) under the title of "The Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products". The initial members of PIC comprised the 10 member countries of EFTA at that time. It was realized in the early 1990s that because of an incompatibility between the Convention and European law, it was not possible for new countries to be admitted as members of PIC. Consequently, the PIC Scheme was formed in November 1995. PIC and the PIC Scheme, which operate together in parallel, are jointly referred to as PIC/S. You can download publications that relate to a variety of pharmaceutical manufacturing and testing issues.



United States Pharmacopoeia
www.usp.org

This link is directed to the homepage of the United States Pharmacopoeia. It provides some general information including USP news, drug and dietary supplements, and products. It also provides an online catalog to order USP 24 and its supplements. Certain chapters are more relevant to isolation technology than others, such as: <71> Sterility Tests, <1035> Biological Indicators, <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments, and <1208> Sterility Testing – Validation of Isolator Systems.

Posted by Tim Sandle