Certainly one of the most sophisticated instruments available to our industry, Pyroskinetix has the ability to not only detect the presence of endotoxins in a sample or group of samples, but also to quantify the levels of endotoxin present. It is far more rigid than any of its predecessors, requiring a standard curve of six data points. And samples are again submitted in duplicate — both spiked and unspiked.   

Although most contract labs that I work with own an instrument similar (in stated function) to Pyroskinetix.  However, many pharmacists purchase endotoxin testing “kits”. These simplified kits are “knock off” or generic versions of the Pyroskinetix methodology. Most do not follow the US guidelines for endotoxin testing.  It’s basically “shake and bake”…you put a small portion of your drug into a test tube, which is then placed in a heating device – one that may or may not necessarily conform to the test itself — and after a certain period of time, the pharmacist receives results indicating positive or negative for the presence orabsence of endotoxins.

Most compounding pharmacies are content to use these broader-based, far less refined generic methods. They will attest to performing BET regularly, yet are – by and large — seemingly unaware that the generic tests will frequently deliver a false negative. 

There are those who would ask “Why? Why did I  –– go that far…purchasing expensive equipment that wasn’t specifically required for me to purchase? Because it was the right thing to do. Bottom Line: this sophisticated testing tool gave me the ability to enhance my existing testing program. Because we have Pyroskinetix in place, we consequently test more frequently and more extensively and more effectively to verify that we’re operating well within the accepted safety standards. My first BET had a detection level of 0.03 Endotoxin Units (EU) per milliliter. My new BET detection level is .001.

I’m quite proud of my endotoxin testing program – as well as the hand-picked, extensively trained technician who runs it. With testing and staff and standards like that, Hartley Medical Pharmacy can safely say that our intrathecal drugs are carefully tested to ensure that they help everyone…without hurting anyone.

Endotoxins are small impurities present in bacteria. They are actually sections of bacterial walls – more specifically, sections of gram-negative bacterial walls. They are also very lethal and detrimental to the human body. As such, they receive careful consideration in the compounding, manufacture and administering of parenteral preparations. BET is performed on all commercially manufactured parenteral products.

As a college student, I developed a strong interest in parenteral drug therapy and (by association) endotoxin testing. Up until 1982, said testing employed rabbits as the primary test subject – either three or five. The drug was injected into these test rabbits, the resultant body temperature changes (or lack thereof) monitored by a well placed thermometer. If the body temperature varied 0.5 ° or more, the test element was considered pyrogenic – “fire generating” (causing fever) – and indicated the presence of endotoxins.

Allow me to digress here by explaining that in those early days of endotoxin testing, endotoxins were referred to as pyrogens –  until it was discovered that not all endoxins are actually pyrogenic. The distinction was made, and the use of “pyrogen” synonymously with endotoxins was discontinued.

Cued by this revelation and the ongoing evolution of available technology, in 1982 an innovative new endotoxin test was developed. I followed its development over the years as I developed my practice, learning more and more about the nature and specifics of this new testing method. In 1998, I contacted a company – one of only three that manufactured the endotoxin test at the time – Massachusetts’ Associates of Cape Cod. (www.acciusa.com )

Key to the testing was a lysate – an enzyme — known as LAL (Limulus Amebocyte Lysate). Derived from a HORSESHOE CRAB [Limulus polyphemus] found only on the eastern seaboard of North America along the various coastal bays of Massachusetts and Connecticut and Japan, the lysate acts to clot and expel bacteria with which the horseshoe crab comes in contact. The crab species has been around for about 250 million years, and for all this time, the lysate has served as the creature’s immune system. Someone researched this phenomenon and found that this lysate has affinity to the lipopolysaccharide section of bacterial cell walls.

Entranced and engaged by this story and its implications for the field of intrathecal drug therapy, in 1999 I pulled the trigger. I bought the equipment that would make it possible for me to conduct my own bacterial endotoxin testing.

This test was very specific and very complicated. We compounded our drugs, took samples and injected the lysate into the test tubes, but there was more. You had to perform a standard curve. The rationale for the standard curve was to ensure the lysate reaction worked with a cross section of endotoxins concentrations.  If that standard curve played out correctly — if the mixture clotted — you said “OK, I’m prepared to submit samples of my active drug.”

We tested our samples in duplicates. This discipline of not only running a standard curve, but preparing samples in duplicate – both spiked and non-spiked  — took us to a new level of “You’ve gotta be kidding”…and a new level of expertise in analytical chemistry. We explored and learned and grew – and, in time, we mastered this sometimes maddeningly complicated procedure.

We continue to administer this test on our compounded preparations, with new advanced instruments – and it has made all the difference in our finished product.  We learned volumes about our preparations and how they interacted with the enzyme – how they actually effect the way the enzyme can enhance or inhibit the outcomes – and we turned that knowledge and know-how into a significantly serious service asset, for our company, our clients and their patients.

He then had them repeat the study on a separate day under identical conditions – except for the fact that he had them wipe their hands with alcohol after filling every third syringe.  The Contamination rate dropped by about 2% — simply from wiping their hands down with alcohol more frequently.

At a recent conference held by the AAPS (American association of pharmaceutical scientists) my attention was drawn to pharmaceutical manufacturing booth. Inside the booth was a large TV screen playing a video of people – dedicated quality assurance technicians — properly gowned and undertaking a very high risk, high-purity-parameter task. Their actions so pure and perfect and powerful that it was hypnotic.

In the video, I observed individuals filling vials with drugs, much in the same was as we do at Hartley Medical. The next step, however, was both impressive and surprising. When the person finished with the machine, she walked into another room where another technician was waiting. The technician took a plate about the size of the palm of your hand – a growth plate— and removed the lid, extending it out to the other technician, who took their fingertips and applied them to the plate in order to see what bacteria might be present as a result of production involvement. This highly refined and analytical process is done in the exact same way at Hartley.  

This test is simply known as Fingertip Assessment – and will soon be shown on our own Hartley Medical website.  It is an integral part of the unequalled service profile that we pride ourselves on here at Hartley – the ensuring of uncompromising quality in our solutions and our environment.

That being said, it is important to note that the current industry standard requires you to perform a Fingtertip Assessment once a year.

Yes, I said “once a year.

What’s more, the USP 797 rules governing Fingertip Assessment allow for the testto occur immediately after one has washed and placed on sterile gloves. Performing the assessment in such a short time frame allows for almost no contamination to occur, and therefore shows very little, if not nothing, about the actual cleanliness of the facility.

Contrast this procedure with what we do at Hartley. We perform Fingertip Assessment our staff between the hours of 1 and 5pm — during active use. We recognize that as soon as you reach for a syringe, a needle, a vial… the operation becomes suspect and your previously aseptic gloved fingertips might be contaminated. This is why we wipe our hands down every other preparation – constantly scrubbing hands with alcohol. And this why when we perform random Fingertip Assessments throughout the work day, we can be confident that the results genuinely reflect Hartley’s quality.

In many ways our objectives are simple: to keep the contamination rate down throughout the process of sterile compounding; to maintain an absolutely minimum bio-burden; and to provide the absolute highest quality care. 

                         That is quality assessment. That is Hartley Medical.

More than ten years ago, I considered purchasing an analytical device called a HPLC – High Performance Liquid Chromatography. It’s more than just the latest thing … it is literally straight out of C.S.I.  In all the CSI dramas, the lead investigator has a lab person that can tell you the exact number of micrograms of poison in the concoction used for the demise of the latest victim. The HPLC is the equivalent of that guy.

At that time, I was dissuaded by others who cautioned me:

 “Don’t do it. You don’t need it … too sophisticated.”

 “Too expensive.”

 “Too costly to run … and you’ll need to hire a technician just to operate it.”

 So I shelved it.  

My first exposure to the HPLC was in college when it was introduced in a chemistry lecture. My professor said at the end of the lecture, “The next frontier is HPLC.”  I remember saying to myself  “I’d really like to be able to do that.”

It’s gratifying when the impressions and judgments we make at earlier times in life come back and are confirmed.  I’m happy that the goals I developed during my encounters with organic chemistry, and pharmaceutical medicine and technology, are now realized. Twenty years later – at the end of a year-long process of investigation and working with a seasoned pharmaceutical consultant – I took a leap of faith and purchased a state of the art HPLC device.

The dream is now an analytical reality. To my knowledge, Hartley Medical is the only intrathecal drug provider that has this in-house capability.

The HPLC has opened up a whole new world of quantitative analytical chemistry, as well as quality control possibilities.  With the HPLC, we can quantify the number of milligrams per unit of volume and the accuracy of final compounding of products for patient administration. We can determine the exact levels of morphine in compounded preparations – and not to the standard plus or minus 10%, but plus or minus 2 to 5 %. We have the ability to tell you exactly how much caffeine is in your morning cup of coffee.

We have often been approached by clinicians and physicians to conduct studies long overdue, but which are now accomplishable. We have achieved a new level of quality control, a new standard of accuracy … and yet we’ve still only scratched the surface of possibility and potential. I look forward in the months ahead to keeping you informed of our progress.

There is, most assuredly, a widespread assumption out there that all pharmacies are pretty much the same…and that they’re doing everything that they should (or could) be doing to provide optimum quality products and safety assurance.

They’re not.

When you consider how many such companies are out there in the United States – one on every corner virtually — that percentage speaks compellingly to how far the industry has to go. It is appalling in a very real sense, considering how important quality control is to any business – but particularly when you’re talking about the health (sometimes a life or death consideration) – of the client (patient) involved.

 Most pharmacies have a pharmacist and maybe two or three clerks or ancillary staff – the bare minimum. I’m sure most will tell you they don’t need any more than that…or that it would be nice if they could afford a quality control person. I know of only two pharmacies in the United States that have them.

 The fact is, they really can’t afford not to have one. This position has been an integral aspect of Hartley Medical for the last seven years…and their job has expanded.

 Our Quality Assurance Staff check our compounded preparations to make sure they are free from bacteria and endotoxins – impurities that are detrimental when in contact with human tissues.

 Duties include the performing of environmental monitoring for bacteria and viable and non-viable air particulates. We utilize two different instruments to constantly evaluate and maintain the cleanliness of our compounding environment:

 1) ACTIVE AIR SAMPLER — an industrial “dust buster” that brings 1000 liters of air across a growth plate that is about 50 millimeters wide. The device actively draws in the air across this device to obtain a qualified sample and to assess “bio burden.”

2) LAMINAR AIRFLOW WORKBENCH (aka LAFW OR IV HOOD) — a work service device that expels filtered air across a 6ft x 3ft sterile area defined by plexiglass walls and a hood above. These are actually work surfaces upon which we compound our sterile preparations. Standard is a Class 100 – filters 100 particles at .5 microns per cubic foot. We use a Class 10, which is cleaner by a factor of ten. Our IV hoods are tested every 120 days and certified by an outside lab. The industry standard is every 180 days…and before 2008 it was once a year.

 We use the IV Hood to ensure a greater degree of certainty of cleanliness in all that we do…and all pharmacies should use them as well. So many practices and practice-employed instruments operate under the implied assurance of an eternally sterile environment…but it is not always so.

 Ronald Reagan once said, “Trust, but verify.” We live that motto at Hartley Medical. The only way to ensure a sterile environment is to test it… and continually test it after that.

 Our Quality Assurance Staff verifies. We have never compromised the purity of our compounding or our compounding environment because we control said environment so completely and so carefully…trusting, but verifying.

Why is it so difficult for other companies to get on line with this essential function?

 Cost. But here we’re really talking about owners who work at the bare minimum vs. those who reinvest in and actually grow their business.

 Why is the public so reluctant to demand this assurance from their pharmaceutical providers?

 They simply don’t know how important it is.

 Well, I’m here to tell you that it is.

 I bought that printer – at first sight. I wanted that kind of quality evidenced in every printed piece that represented – and reflected – my efforts for my clients.

 •                       •                       •

 November marked the year-in-operation anniversary of our new Hartley Medical digs, and most importantly, our Clean Room. Particularly gratifying to me because, way back then, the decision to undertake so monumental an upgrade was not to be taken lightly. We took a risk – financially and professionally – and we have worked hard and we are, as a result, far ahead of the curve (and of where we projected to be by this time). Thankfully way ahead – and that is definitely cause for celebration!

 The Old Hartley was 1700 sq. ft. with a 300 sq. ft clean room. Sparked by growth and demand and desire (the desire to achieve the pre-eminent level in clean room excellence), we searched for roughly 18 months and found the new home not far away (about 3 miles). The new facility? 7000 sq ft . The new clean room? 700 sq. ft.

Our clean room is divided in three: a gowning room, a prep room, a sterile preparation area. Apart from its size, the unique features of this tri-sectioned clean room (apart from it’s size) are its employed air management systems and its legitimately state-of-the-art filtration systems which remove both viable and non-viable particulates.

 In our advanced filtration system, the air contained in the room recirculated, and then filtered again and again continuously to truly (and significantly) marginalize the chance of contamination – at a rate of 190 ACH (Air Changes per Hour). The industry standard is 30 ACH.

 Easily 95% of our competitors don’t have this…don’t even come close to this. Most are afraid to incur the cost of such a facility, although they certainly recognize the need and advantage and salient benefits of having one. We take very seriously the technology needed to be put in a place to ensure an accurate and sterile compounded preparation. That’s why we made the leap in the first place.   As a result, we’re not just “nosing out’ the competition, we’re three or four “laps” ahead.

 It wasn’t easy. It was expensive. It did require serious sacrifice. But it was time. Mistakes in this industry are often measured in human misery…and no one wants to go there. I don’t want to go there.

 In retrospect, one year later, it was the necessary thing to do – the right thing to do. In this business, the necessity for this level of commitment is very real.

 It’s all about reinvesting in yourself . It all about quality assurance. Much is made by other companies about how much the competition put into R&D…but that is the kind of spurious posturing logic that has the dangerous effect of minimizing (and often ignoring) the necessity – the common sense priority – of ensuring the highest level commitment to accurate, sterile compound preparation.

 I will always choose the laser printer…because that’s what it takes. Some are gravitating toward what I have done, but the majority either don’t care, or don’t have a clue. There is no regulatory pressure for them to do it. We did it anyway. All things according to The Hartley Standard. We have made the commitment to excellence and we are successful.

This reimbursement reduction for “J3010,” hydromorphone, may make it difficult for many physicians’ pain practices to continue to provide this pharmaceutical to their patients in this convenient, comfortable, and cost-effective office setting.

Sharing your experience will help illustrate the effect CMS’ reduction in reimbursement has on your ability to provide this therapy to patients in the office setting. Please describe the impact on your practice and patients in an email to stoppain@hartleymedical.com. To protect your patients’ privacy, do not include identifying details or names. I will follow up with you or your office staff to gain permission to post the consequences of this action.

William and Gordon Stuart at their booth during the NANS Conference in Las Vegas.

I recently attended the NANS (North American Neuromodulation Society) Conference in Las Vegas, Nevada. Attending the conference were physicians, scientists, and vendors from all corners of the globe. I was able to attend many of the offered lectures, including those on reimbursement, granuloma detection and management, intrathecal drug pharmacokinetics, and management of IT therapy side-effects. Among the speakers were Lynn Webster, Tim Deer, Tony Yaksh, Johsua Prager, Richard Rauck, and Lisa Stearns. The conference allowed me to connect with current clients, as well as to reach out to potential clients, including international pain management physicians. Most importantly, however, I was able to communicate to those at the conference Hartley’s new facility, as well as the capabilities and improvements that have come with it. I strongly encourages all those involved with interventional pain management to attend next year’s meeting. You will not be disappointed.

I recently attended an AAPS (American Association of Pharmaceutical Scientists) meeting at the LA Convention Center. I went to hone my analytical skills and to enhance my understanding of analytical chemistry as it pertains to compounded preparation.

 What I found there was essentially a room full of geniuses – 8500 geniuses to be exact (mostly PhDs) – from all parts of the globe. It was a lot like being dropped into a foreign country…without an interpreter. So many languages, so many perspectives, so much advanced technology, so many ways to go and options to explore.

 Awesome. Inspiring. Perception-altering. 

 I gotta tell you, this one-day foray into viewing the courses and equipment available was at once overwhelming and supremely motivating. It brought to mind the double-edged question:

 So you wanna be a ROCK STAR?!

 I do. I’m interested in manufacturing pharmaceuticals and also in understanding more about how aseptic pharmaceutical packaging is accomplished. I’m exploring my options — searching out better ways of qualifying and quantifying my work. I’m not a rock star yet, but I did make some contacts, and I did see many wondrous things. For instance…

 Picture this; a technician in a specialized clean room (similar to the one we have at Hartley Medical) – wrapped, gloved, full body suit, boots. The technician watches a machine fill vials with an injectable drug, reviewing its output. The technician then leaves the specialized room, walks into an aseptic packaging room where a similarly “wrapped” technician awaits. It is that technician’s job to assess the aseptic conditon of the first technician, touching the contact plates, right and left and then touching the top of the woman’s head to ascertain the presence of any bio burden. Then both move on to the next task. It was a beautiful thing, a powerful thing – and quite spiritual in its own way.

 Yes, spiritual. The powerful imaging of people properly gowned and undertaking a very high risk, high-purity-parameter task. A dedicated quality assurance technician. All sequenced into a tightly environmentally controlled process. Compared to current standards in our industry, this standard of care and attention to detail is off the charts.

 ROCK STAR Stuff.

 And that’s the way that it should be done. I was very gratified and moved to see it happen and to see so much made of it – because that is the level of quality control and practice excellence I have always striven to achieve in my operations.

Over the years, I’ve received numerous calls and questions regarding the chemical characteristics of intra-thecal medications. In answer to these queries, I’ve decided to get the ball rolling by sharing some published information with you – on solubility and syringe composition limits – information that I believe will prove of some value.

Maximum Solubility of Common Intraspinal Drugs at Room Temperature (21° C):

Baclofen: 5.0 mg/ml
Bupivacaine HCL: 40.0 mg/ml
Clonidine HCL: 76.0 mg/ml
Fentanyl Citrate: 25.0 mg/ml
Hydromorphone HCL: 250.0 mg/ml
Morphine Sulf.: 64.5 mg/ml
Sufentanil Citrate: 25.0 mg/ml

As most of you out there are aware, the drugs noted above are maintained in the pump’s reservoir at 37° C. Solubility of IT meds is affected by additional drugs contained within the mixture.

OUR TAKE: Poly pharmaceutical solutions will interact and thereby alter certain chemical states of the combined drugs. For that reason, we do not recommend maximizing the drug concentration when used in combination with other agents.

Obviously, the maximum concentrations of these pharmaceuticals exceed clinical applications. The chart below shows the lipid solubility and equal analgesic conversions when drug alternation is required. Please keep in mind, this is a guide – and that thorough understanding of each drug is necessary prior to dosage change.

Intra-thecal Analgesic Properties / Dosing Conversions

 Questions? We’re happy to address them. Just contact me at wstuart@hartleymedical.com or call our office at 562.595.7548.