BioScience Laboratories, Inc., personnel participate in the activities of numerous national and international professional associations that focus on microbiology and infection control in the healthcare and food service industries.  As our website indicates, our interests relate to disinfectant and topical antimicrobial formulations, their importance in reducing the risk of disease transmission, and fair assessments of their antimicrobial efficacy.  Because such assessments require methods of testing that provide reliably reproducible data meaningful in the context of infection control, our personnel have, for many years, been deeply involved in method development through the American Association for Testing and Materials (ASTM), specifically, Subcommittee E 35.15 on Antimicrobials.  Four members of our staff, including myself as Subcommittee Co-Chair, serve on E 35.15.

As of the conclusion of our semiannual meeting last week, our Subcommittee has 96 members and is responsible for 45 approved methods, plus another 13 currently in the process of development.  In the interest of brevity, I will describe only two examples of the latter.

The first of special note is a modification of E 1174, the ASTM version of the FDA method specified for testing of handwash products intended for use in healthcare. The modification involves the procedure for contaminating the hands with Serratia marcescens, the indicator bacterium used to challenge product antimicrobial efficacy, and is particularly important in that the new method will be much more appropriate for testing leave-on (non-water-aided) hand sanitizers.

Another method-in-the-making is one for testing liquid microbicides versus bacterial biofilms, organized assemblages that are considerably more resistant to antibiotics, topical antimicrobials, and disinfectants than are planktonic (free-floating) bacteria.  Only in the last decade, or so, has the important role that biofilms play in disease causation and environmental fouling been understood, and colleagues from the Center for Biofilm Engineering at Montana State University here in Bozeman have been in the forefront of methods development in E 35.15.

Although I have selected for comment only these from among our many methods, I would welcome any questions you may have about testing of antimicrobial formulations and how the testing methods are created collaboratively by volunteers from industry, regulatory agencies, and CROs such as BioScience Laboratories.

– John Mitchell, Director of Quality Assurance and Chief Medical Officer

As required by <USP 1072> clean-room disinfectant validation is required “to demonstrate the efficacy of a disinfectant within a pharmaceutical manufacturing environment”.

What you must do:  Take the time to think through all the parts and pieces that make up your overall cleaning program to ensure the program is effective, practical for every day activities.

Product Selection:  

Alcohols:  Broad-spectrum efficacy against vegetative bacteria.  Typical concentration of 70% used.  Not effective against molds or spores. 

Aldehydes: Powerful and aggressive disinfectants.  However, are highly toxic to personnel and require long contact times for sporicidal claims.  

Sodium hypochlorite (NaOCl) and other chlorine compounds:  Broad-spectrum biocidal activity.  Chlorine solutions are corrosive, unstable over time, and rapidly lose activity.  Typically concentrations for sodium hypochlorite are 500 to 50,000ppm.  A low ppm will be effective against most vegetative bacteria within 10 minutes.  Unfortunately, to kill spores/molds the concentration must be greater.  Good disinfectant – Poor cleaner.  Will not remove soil load.   

Hydrogen peroxide: A potent biocide and environmentally friendly.  Peroxides are deactivated in the presence of soil loads, so pre-cleaning is required to achieve the desired reduction in the microbial population.  Typical concentrations as low as 0.5 percent.  Hydrogen peroxide can be combined with other ingredients to dramatically increase its germicidal potency and cleaning performance.

Phenolics: Broad range of disinfectants that are used on environmental surfaces. Typical concentrations are 2 to 5 percent with contact times of 5 to 10 minutes.  Added detergents are effective in removal of soil loads. 

Quaternary ammonium compounds: Non-irritating and non-corrosive to surfaces.  Typical concentrations of 0.1 to 2 percent and require 10 minutes of contact time to kill microorganisms.  However most are not effective in removing biofilms and leave surfaces with a residue that must be removed after disinfection.

Application Procedure:

A spray procedure is a quick way to effectively treat a surface.  However, with many of the disinfectants a pre-clean may be required to remove any soil load.  A wipe procedure is also very effective in mechanically removing microorganisms and is a great addition to any disinfectant cleaning program.

How can BioScience help?

We can perform the following testing (1) use-dilution tests (screening disinfectants for their efficacy at various concentrations and contact times against a wide range of standard test organisms and environmental isolates); and (2) surface challenge tests (using standard test microorganisms and microorganisms that are typical environmental isolates, applying disinfectants according to your cleaning procedures. 

– Liv Graving, Microbiologist and In-Vitro Study Director 

We have been very fortunate in the past regarding results from FDA, EPA, and Sponsor audits.  We take each one seriously, as a learning experience, and implement appropriate changes to our processes in a timely fashion.  The audits are a constant reminder for BioScience to strive to be the best that we can be.  Although we are not ISO 17025 certified, we have been audited using those guidelines, as well as Good Laboratory Practice Regulations (GLPs) and Good Clinical Practice Regulations (GCPs).  Some outcomes of the audits have included: adding “Controlled” and “Uncontrolled” stamps on copies given to auditors; adding “Obsolete” on documents once a revision has been put into place; and being more diligent in referencing other SOPs in our SOP documents.  We are accommodating in sending, prior to an auditor’s visit, such information as our current organizational chart, corporate resumes for key employees, and the index of our Standard Operating Procedures.  We have received praise on the ease with which we are able to access documentation requested by an auditor.  All in all, each audit has been a positive experience for us, and I believe for the auditor as well.  Come visit us and see for yourself.  Scientific Expertise with Montana Hospitality is a self-appraisal we take very seriously.

Amy L. Juhnke, Manager of Quality Assurance/Document Control

For those wondering about the responsibilities of a principal investigator, here is the result of my research on this topic.

The Principal Investigator receives no direct supervision and has complete authority and responsibility for the clinical trials they perform. Personal initiative is imperative. He or she must have a firm understanding of the principles of planning, organizing and management. The Principal Investigator must promote Good Clinical Practices thought the clinical research process by ensuring strict adherence to the protocol, protection of the patient’s health and welfare, integrity of the data generated, and compliance with all federal and state regulations The person who holds this position must have a current physician’s licensure to practice with five to eight years of experience in clinical research. They must have an above average ability to interface with patients, staff, sponsor, and IRB. The Principal Investigator is responsible for maintaining a cohesive team that consistently completes clinical trials on time and at budget.

Provides investigator qualifications and agreements to sponsors by maintaining current curriculum vitae, demonstrates the proper education, training and experience to conduct the clinical investigations Principal Investigator is responsible for signing Form FDA 1572, the protocol, and all sponsor contract(s), and complete disclose of any conflicts of interest

Ensures protocol compliance by possesses a thorough understanding of the protocol, determines if the inclusion/exclusion criteria are compatible with the intended study population, establishes recruitment goals and gains approval of both the IRB and the sponsor prior to any amendments or protocol deviations

Ensures continuous oversight of the clinical trial by the IRB, by providing the protocol, investigator’s brochure, informed consent, recruitment materials, protocol amendments or deviations, adverse events and any other materials regarding the study to the IRB for review

Ensures adequate facility and number of staff to conduct the study and makes adequate time to supervise and conduct the study.

Manages medical care and ensures that all medical decisions related to the clinical trial are made by a qualified physician. The Principal Investigator evaluates subject compliance and response to therapy, is responsible for adverse events, proper medical attention in the occurrence of an adverse event, and notification of primary care physician

Protects the rights and welfare of subjects ensuring the informed consent is in accordance with CFG 56 and 45 and that the subjects are aware of all aspects of the clinical trial

Oversees the quality of the trial by ensuring all case report forms are legible, complete, and accurately reflect the source documents. Reviews, understands, and approves corrections made to case report forms and ensures the proper quarantine and use of the investigational materials

Communicates effectively with subjects, the research team, the sponsor, and the IRB and is responsible for the clarity of the protocol and purpose of therapies by the research staff. The Principal Investigator will participate in study monitoring conducted by the sponsor and regulatory administrations

The Principal Investigator maintains professional knowledge and technical expertise by reviewing medical research publications and participating in professional organizations

John Dyba, Senior Account Executive

The American Medical Association (AMA) will be considering a resolution at their House of Delegates meeting in Chicago on June 13-17 to address the role of clothing and accessories (neckties, jewelry, wrist watches, etc.) in the spread of pathogens in hospitals. Resolution 720 advises that hospitals adopt dress codes that “minimize transmission of nosocomial infections, particularly in critical and intensive care units.”

The resolution also specifically refers to the United Kingdom’s “bare below the elbows” policy.  If passed, such a resolution would cause a major fashion change in hospitals — no more long sleeve white lab coats. The proposed resolution is expected to help healthcare workers be more compliant with hand washing guidelines, as there will be less concerns about getting jewelry, wrist watches and long sleeves wet.  Avoiding wet shirt sleeves and wrist jewelry is one of the driving forces behind using alcohol-based gels. What have you heard from your customers reagarding this resolution?  If passed, do you think this will change the demand for alcohol-based hand sanitizers?

As a clinical research manager conducting research on a vulnerable population particular attention must be given to the process of informed consent. This additional attention is required because vulnerable populations are populations who have limitations regarding their ability to provide informed consent and are more susceptible to coercion or undue influence. Because the decision to participate in clinical research must be made by a competent individual who has received the necessary information, and who has understood that information, special care must be taken to resolve language and comprehension barriers between the researchers and their potential subjects.

Therefore the researchers must set aside adequate time and resources to insure that the proper language, or languages, is used to inform the potential subjects of the requirements of informed consent. Not only should the language itself be presented at a comprehension level easily understood, but the content and concepts of the message must also be presented at a level that will allow their comprehension. Particular attention should be given to the concepts of clinical research, randomization, and inactive medications (placebo) due to complexity of the issues, their importance, and the relative inability of the normal population to completely comprehend them.

Each of these issues requires the attention of the Institutional Review Board (IRB). It is the responsibility of the IRB to determine that the minimal requirements of 45 CFR 46.111 are achieved, that additional safeguards for this vulnerable population are in place and that proper informed consent is obtained from each subject, prior to protocol approval.

Private, for-profit IRBs can function without ethical conflicts as long as their members are not directly involved in the research and the outcome of the review in no way benefits them as individuals.

John Dyba, Senior Account Executive

The U. S. Environmental Protection Agency (EPA) has posted its recommendations for the evaluation of antimicrobial pesticides for their efficacy versus Clostridium difficile.  These products include dilutable liquids or powders, ready-to-use formulations, spray products, or towelettes that are labeled for use to treat hard non-porous surfaces in healthcare settings where C. difficile spore contamination may occur.  The document presents guidance towards the recommended types/methods of testing, the number of product batches and carriers per test, the recommended/acceptable spore strains of Clostridium difficile, and product performance criteria.  Examples of allowable label claims for products meeting the acceptance criteria are also given.  To view the EPA’s recommendations visit http://www.epa.gov/oppad001/cdif-guidance.html.

Terri Eastman
Manager of In Vitro Laboratories

The history of clinical research has followed a very similar path in the industrialized countries of the world: Initiation, Acceleration, Rationalization and Harmonization.  The understanding that controlled clinical research would need to be conducted to evaluate the safety and efficacy of therapies prior to public use was eventually reached by all of the industrialized countries. During the 1960’s and 1970’s many laws were passed regarding the evaluation and reporting of drug safety, quality and efficacy. During this time the drug industry was becoming more international and seeking to market their products globally, but the process was slowed by the requirement to register each product nationally. Therefore, the same fundamental research was being required by each regulatory system to show product safety and efficacy. This requirement stemmed from technical requirements within each regulatory system that caused expensive and time consuming research to be duplicated on drugs that had previously been proven safe and effective. Concerns regarding the cost of duplicating research and increasing health costs while slowing the availability of therapies that are safe and efficacious to patients who needed them could be reduced through regulatory harmonization.

Harmonization of regulatory requirements between countries was pioneered in Europe in the 1980s and proved that it was possible. Discussions between Europe, the US and Japan progressed to plans of action in 1989 and the International Conference on Harmonization became a reality in 1990.

Harmonization objectives are divided into three topics: Quality, Safety and Efficacy and represent the basis of therapy approval. Expert Working Groups (EWGs) were formed to discuss the scientific and technical issues regarding each of these topics. The initial objective of the ICH was to remove duplication and redundancy in the development and review process by defining data sets that would demonstrate quality, safety and efficacy of investigational therapies. Over time the ICH has developed the Common Technical Document (CTD), this document provides the harmonized format and correct content for international product applications. 

Today the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) attempts to gain consensus between the regulatory authorities of Europe, Japan and the United States by involving experts from each region to discuss scientific and technical issues regarding product registration.  The purpose is to make recommendations on ways to achieve greater harmonization regarding the interpretation and application of technical guidelines and requirements for product registration to reduce the need for duplicate testing during the research and development of new therapies. The result of effective harmonization is the more economical use of human, animal and material resources, and the reduction of unnecessary delays in the global development and availability of new therapies and maintaining quality, safety and efficacy. This approach represents the proverbial three legged stool and will simply not work without all three topics (Quality, Safety, and Efficacy) addressed correctly.  This approach has provided the ICH with success because it harmonization was/is developed on the foundation of scientific consensus from both the industry and the regulatory associations from each of the three regions.                                 

John Dyba
Senior Account Executive