RASIG meeting
A meeting on Regulatory issues will take place on March 9, 2010. This meeting will be chaired by Jeff Solate and Chris Newman. The topic is “Medical device reporting and corrective action with reference to USA QSR, Canada’s ISO and Global harmonization standards”.

Meeting facilitator
Jeff Solate is a regulatory compliance specialist with over 25 years experience in the US and Canadian medical device and pharmaceutical industry. He is currently writing 2 books in the pharmamedical fields. JTS & Associates specializes in regulatory compliance training, FDA PMA, EU C E Mark, Health Canada’s CMDCAS, regulatory submissions, post-design, clinical, regulatory clearance for medical device, pharmaceutical, hospital & cosmetic products.

Medical Device Reports
Medical device reports (MDRs) are the mechanism by which a user-facility such as a doctor's office, medical centers, surgical centers, hospitals, nursing home and long-term care centers' etc, report device-related events to regulatory agencies, device manufacturers, suppliers, marketers, importers and exporters.

An individual medical device report (MDR) si filed with the FDA, Health Canada or EU Medical Device Agencies when a device may have caused, contributed to a death or serious injury, or when a device malfunction would likely cause or contribute to death or serious injury or or when the event re-occurs.

The March 9 meeting will discuss questions related to device reporting as it impact on a regulatory person's attempt to comply with Class I, II and III medical device reporting and corrective action issues.

The world is changing fast. Various regulatory authorities around the world are struggling to keep up with new products and procedures by constantly coming up with new regulations and modifications to existing regulatory processes. What are Ontario SMEs to make of all this?

TMTA’s RASIG (Regulatory Affairs Special Interest Group) met on March 17, 2009 to discuss various regulatory issues facing most medical technology manufacturers in Ontario. The meeting was facilitated by Roger Leclerc , Senior Director of Regulatory Affairs for Medical Devices & Biosciences Int’l.

Armed with a PowerPoint presentation, Roger started the meeting by making the point that medical device companies are increasingly facing the following challenges;
1. rapid technological advancement
2. increased emphasis on the safety of patients
3. a growing insistence on the need for transparency
4. the need for an improved management of resources

Roger talked about how the need to keep up with emerging technologies is accelerating the modernization of current Medical Devices Regulations.  He invited participants to consider how these developments are impacting medical devices companies. The group discussed what measures will likely be needed to ensure that patient safety is not compromised.  

Roger also explained how the process of rebuilding medical device programs is evolving and changing the current healthcare environment. EHEHHe then invited participants to consider how these changes will impact the future of medical devices companies in Canada, USA, Europe, Australia, and Asia.

The group discussed how growth of smart technologies is resulting in the emergence of new medical devices and altering the use of existing devices. This process is expected to accelerate even more over the next few years. Among the trends identified are: the growth in computer related technologies, molecular medicine, homecare, self-care, minimally invasive procedures, molecular biology, nanotechnology, organ replacement, assistive devices using hardware and tissue-engineered components. Other trends also impacting the medical device industry: the drive to lower costs, device customization, prevention-orientation and evolving patient attitudes.

Background:
The risks of DEHP have been known for many years

As our industry knows, it has been several years since the Medical Devices Bureau of Health Canada has issued a warning about the hazards posed by Di(2-ethylhexyl) phthalate (DEHP) leached from medical devices.

DEHP (Di(2-ethylhexyl) phthalate) is a chemical additive used to soften a wide variety of medical devices made of polyvinyl chloride (PVC) plastic, including catheters, tubing and bags used to administer blood, plasma, drugs, and other fluids. DEHP can leach from the PVC plastic into the fluids that come into contact with it.

Laboratory research has shown that exposure to DEHP results in a wide range of adverse effects in rodents and other animals, including adverse reproductive and developmental effects. DEHP is thought to have the potential to produce similar adverse reproductive and developmental effects in humans. Of greatest concern, are the adverse effects on the developing testes of young animals.

While there is no conclusive data on the toxicity of DEHP or its metabolites in humans, there are reports in the medical literature of a variety of adverse effects seen in patients exposed to DEHP from medical devices. These effects concern male primates exposed orally and intravenously to DEHP during the neonatal, preadolescent and peri-adolescent periods, which are believed to be the most sensitive periods for testicular toxicity. The possibility of adverse effects from high exposures in potentially sensitive humans can therefore not be conclusively ruled out at this time.

Although there is no data on the reproductive and developmental toxicity of DEHP or its metabolites in humans, the mechanism by which developmental and testicular toxicity in particular occur in rodents appears relevant to humans. The animal data indicate a possibility of developmental and testicular toxicity, particularly in young human males exposed to high levels of DEHP, and support risk management measures to limit exposure to DEHP.

Protection of susceptible populations from DEHP exposures at levels that may pose significant risks is warranted. A viable option is a balanced risk reduction strategy, in which the risk of adverse effects from exposure to DEHP are balanced against the benefits of DEHP-containing medical devices.

The greatest concern is in humans where the susceptibility of the patient and exposure are both high. In these situations, the use of alternative products is justified as a prudent cautionary measure. Individuals who are not as susceptible are less of a concern, but also merit consideration for the need for alternative procedures in cases of high DEHP exposure.


Some people are more at risk than others
The subgroups most susceptible to adverse effects of DEHP exposure are male newborns (particularly prematures) and fetuses, male infants and young children, and (possibly) peripubertal males.

Some medical procedures may result in relatively high DEHP exposures. These are:
- exchange transfusion in newborns and infants
- extracorporeal membrane oxygenation (ECMO) in newborns and infants
- administration of lipid-containing total parenteral nutrition therapy (TPN) solutions to newborns and infants
- enteral nutrition (lipid-containing solutions) in newborns and infants
- multiple intensive care unit (ICU) procedures in sick newborns
- intravenous (IV) infusion of lipophilic drugs or drugs which contain surfactants
- cardiac surgery in newborns and infants
- ECMO and associated blood transfusions in adults
- cardiopulmonary bypass in adults
- artificial heart transplant in adults
- coronary artery bypass in adults
- enteral nutrition in adults
- trauma patients receiving multiple blood transfusions

The use of DEHP in the following subgroups may put these individuals at higher risk:
- volume exchange transfusion in newborns and infants
- ECMO in newborns and infants
- cardiac surgery in newborns and infants
- administration of TPN solutions that contain lipids to newborns and infants
- enteral nutrition in newborns and infants
- multiple ICU procedures in sick newborns
- IV infusion of lipophilic drugs or drugs which contain surfactants

Some precautions must be taken
Based on the current understanding of the science, the Health Canada website listed the following precautions back in May 2003:

1.  Exposure to DEHP should be limited in groups of patients who may be at risk. These are male newborns, infants and young children, pregnant women carrying a male foetus, and peripubertal males.

2.  Healthcare professionals should identify medical devices that contain DEHP.

3.      Alternatives to DEHP should be introduced where there is adequate data on their safety and efficacy.

4.      Medical procedures should not be avoided because of the possible health risk associated with DEHP exposure as the benefits of these procedures outweigh possible health risk associated with DEHP exposure.

5. Use of blood bags containing DEHP should only be continued until an alternative becomes available. For susceptible populations, healthcare providers should consider special strategies and procedures, such as the use of the freshest blood stored at the lowest possible temperature, to reduce exposure to DEHP and its metabolites from blood products.

6. Alternative measures should be introduced as quickly as possible to protect those sub-populations at greatest risk, namely the fetus, newborns, infants and young children receiving volume exchange transfusions, extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass, cardiac surgery, TPN, enternal nutrition, and lipophilic drug formulations.

7. Alternative products already available (i.e., heparin-coated tubing) should be utilized for all ECMO procedures in newborns and infants.

8. Tubing and storage bags used for the administration of lipophilic drug formulations should not contain DEHP, or strategies to decrease DEHP exposure should be employed, particularly when administering these drugs to infants and children. Many manufacturers of lipophilic drugs already recommend the use of non-DEHP plasticised materials for drug administration. Specialty administration sets, bags, and tubing manufactured with non-DEHP materials are currently available for use with lipophilic drugs.

9. As suitable alternative products are already available, (e.g., EVA containers, silicone and polyurethane tubing), total parenteral nutrition solutions that contain lipids should be administered to newborns and infants only via DEHP-free products. Administration of lipidfree TPN solutions, such as dextrose and amino acid mixtures, can be safely done using DEHPcontaining products, as there is little concern about DEHP exposure in patients undergoing these procedures.

10. The IV administration of crystalloids fluids such as normal saline, dextrose, and Ringer's lactate can continue to be done via DEHP-containing products as there is little concern about DEHP exposure in patients undergoing these procedures.

11. National professional health care organizations should develop clinical practice guidelines to reduce DEHP exposure for at risk populations.

12. Manufacturers medical devices made of PVC should take steps to inform users through labelling if the device contains DEHP, since health care professionals need this information to make informed risks management decisions.

13. Manufacturers should conduct research into methods for reducing release of DEHP from products containing this plasticizer as well as into alternatives to DEHP-containing products. Priority should be given to studies that define the real level of risk to humans from DEHP exposure, including research into other possible adverse health effects of DEHP exposure, as well as the safety and efficacy of alternative products.

Many issues remain unresolved

TMTA members and other manufacturers across the country have be waiting for Health Canada's input in this important issue. Many manufacturers claim that they have known about the risk of DEHP for many years and have had alternative medical devices and products available for a long time.

According to them, the problem has been to get the attention and cooperation of hospitals and other healthcare providers. Their focus has been on keep costs down and that has made them very unreceptive to implementing new measures and precautions that would better protect the lives of patients.

In many ways, the situation remains unresolved on many levels. For one, the precautions and recommendations issued by Health Canada are already several years old. And even then, those recommendations fall short of being firm enough or specific enough to be as effective as they could be.

Another major point of contention with the medical technology industry is the fact that while Health Canada requires manufacturers to list the DEHP content of their devices, no limits have been set and no law has been passed requiring suppliers of plastics raw materials to comply.

These issues have been and continue to be of major concern to our industry. For this reason, TMTA's regulatory group will be issuing an official complaint to Health Canada. It will also make specific proposals to bring this matter to a suitable resolution. Stay tuned to this webpage and other bulletins from TMTA.

For medical device manufacturers, safety labels on their products have never been more important. Inadequate warnings could have a wide variety of consequences for the manufacturer as well as its employees, customers and patients - consequences that range from non-compliance to lawsuits to minor injuries or even death.

ANSI and ISO standards
For guidance in the development of safety labels, manufacturers often turn to the American National Standards Institute (ANSI) and the International Organization for Standardization (ISO). ANSI and ISO standards are very similar. Manufacturers typically use one or both sets of standards.

ANSI labels are comprised of four key elements:
- A signal word panel (CAUTION, WARNING, DANGER)
- Hazard identification
- Hazard avoidance
- Consequences of not avoiding the hazard

Standards set by ISO for safety labels include:
- An optional signal word panel
- Hazard pictogram inside a triangle
- Yellow background
- Optional text outlining the hazard and hazard avoidance

At the core of both sets of standards is the actual hazard. Both ANSI and ISO use the following to define the severity of hazards:
- CAUTION: minor or moderate injury may occur (ANSI)
- CAUTION: minor or moderate injury could occur (ISO)
- WARNING: death or serious injury could occur
- DANGER: death or serious injury will occur

Safety Label Design and Development
Several elements go into ANSI- and ISO-compliant safety labels. These include pictorial use; verbiage outlining the hazard, hazard avoidance and consequences; and layout requirements and consistency.

Pictorials
Pictures are the universal language when it comes to communications, no matter a person's native tongue or literacy level. Wherever possible, manufacturers should try to use pictorials to accompany their messages so that end users have the opportunity to visualize the hazard and see how to avoid it without needing to read.

There is a wide variety of standardized pictorials available for use, nearly all of which can be referenced through any number of resources. Use these resources or standards to identify the pictorials best depicting the hazard to be addressed by the safety label as well as pictorials illustrating hazard avoidance - accurately depicting how to avoid the hazard is a key component that is missing in many inappropriately designed safety labels.

Wording
While pictorials provide the important visual component of the hazard, the wording included on the safety label provides more finite detail around the hazard, hazard avoidance and consequences. At this point in the label development process, a manufacturer has already provided the initial wording needed for the label - signal words CAUTION, WARNING or DANGER. The next step is to put the identified hazard into words and describe how do avoid the hazard.

To develop effective wording for safety labels, text must be succinct and use a headline-style format. Label designers must avoid using unnecessary words and present the text in easy-to-read upper and lower case letters. Note that it is acceptable to use all upper case letters in short phrases requiring impact, like MAGNETIC HAZARD.

Next, be mindful of the font size of the text and the space available on the label.

Layout and Consistency
ANSI standards indicate text can be laid out in either a vertical or horizontal format. Both orientations are acceptable design layouts and can be determined by a manufacturer's standards, the area where the label will go or personal preference.

Overall design consistency must be maintained through label design consistency and by using the same pictorials outlined in ANSI and ISO stylebooks.

It is also a good practice to keep layout styles consistent across different labels.

Final Label Design and Production
Once all of the elements are in place, take a final look at the safety label to make sure the artwork is clean and that the label accurately describes the hazard and avoidance steps. It is encouraged to test the label - for example, gather a group of individuals to critique the label on symbol recognition and messaging.

During this testing, it is important for manufacturers to remember that the labels are there to remind the users of what they should have reviewed in the Operators Manual or learned during product training. It is always the responsibility of the user to read the manual and attain training before operating any piece of equipment.

After the label passes the test, work with a proven label supplier to produce the finished product, making certain to provide size requirements and any special instructions to the supplier. In addition, while there are no set standards for the type of material on which the label should be printed, there are special conditions that should be considered by the manufacturer. It is recommended to inform the supplier if the label will be exposed to extreme conditions, such as abrasion or chemicals.

All of these factors will play a role in determining which adhesive, base material and over-laminate (if applicable) are best to use. Other items to be addressed with the supplier are the surface to which the label is being applied:
- Is it curved or flat?
- Is the surface powder coated or enamel paint?
- Does it have a smooth or rough texture?

Discuss, Develop and Improve

TMTA's Regulatory Affairs Special Interest Group (RASIG) is meant to be a forum for qualified Regulatory Affairs and Quality Systems (RA/QS) professionals from regular member companies and organizations.

RASIG focuses on national, international and global regulations that impact the development, quality control, manufacture, approval, auditing, licensing and export of medical devices. Convergent technologies are often a special point of interest at such meetings.

Meetings occur on an ongoing basis to allow members to review common issues, network and learn about changes in the global marketplace. Sessions usually take place in an somewhat informal format which encourages direct participation by all attendees.

TMTA Regular Membership is required for participation in this special interest group (SIG).

Shaping our industry's regulatory future

Scheduled for the benefit of SMEs, this meeting was facilitated by Roger Leclerc who is Senior Director, Regulatory Affairs & Export Development at Medical Devices & Biosciences International. An established expert in the field of regulations dealing with medical devices and medications, Roger started the meeting by inviting each attendee to bring up at least one specific issue of relevance to them.

Each issue was listed on a flip chart and dealt with in sequence. All issues brought up were linked to specific ISO regulations and case histories. The discussion which followed was both lively and informative. Janey Hacke kept minutes of the proceedings. These minutes will be emailed to attendees as soon as they are transcribed. Any qualified member who should have received a copy of the minutes can do so by emailing Marcel Lafleur at marcel@tmta.ca.

Those who participated in this meeting said they got a lot out of it. Attendees requested that another such meeting be held early in the new year so that issues brought up can be studied further. Anyone authorized to take part in such meetings can request a copy of the minutes on the condition that they sign a non-disclosure agreement form referred to in the blue column at the right of this text.

The exact date of the next RASIG meeting has not yet been set but it will be at some point in March 2008. The precise date will be posted on this page as soon as it becomes available.