Not long ago, at a pharmaceuticals convention, I was approached by a doctor who told me that he had, just minutes ago, met one of our quality assurance technician at our booth. He simply wanted to say that he was profoundly impressed by the fact that we had such an individual on our staff – that it was a rarity and a pleasure. I was pleased and proud and concerned all at the same time. Because I know the industry reality that prompted the doctor’s praise.

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.

Remember dot matrix printers? At one time they were the accepted standard for all things printed. Then they came out with Laser Printers. And when you saw it perform for the first time all you could say was…wow.

 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.

AAPS –WANNA BE A ROCK STAR?

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.

ON THE SUBJECT OF INTRA-THECAL PHARMACEUTICALS…

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.

Pain heads the list of reasons Americans seek medical treatment. Yet those suffering from pain often confront an array of obstacles to pain management. This is all the more reason to find a ray of hope in the bravery and advocacy of Casey Matthews, a 19-year-old Southern California student. Since Casey’s mother has been a victim of chronic pain since his earliest years, the impact of this affliction on his life has been immeasurable. However, the student perceived an opportunity to tackle the trauma in the form of the 2009 National Pain Care Policy Act, S. 660.

The proposed Senate bill would, among other things, identify impediments to successful pain care, assess the efficacy of pain treatment and management, and launch an action agenda for eliminating treatment and upgrading training. (Companion legislation, H.R. 756, passed the House of Representatives in late March.) In completing a political science assignment, Casey produced a video in support of the above measures. He is also delivering to the Senate a petition calling for urgent national action to combat pain and thereby improve the quality of life for millions of Americans. (To see the video or sign the petition, visit the American Pain Foundation at www.painfoundation.org/.) I strongly urge you to sign Casey’s petition; such expressions of collective support for attacking the problem of pain are of vital importance at a time when the debate over reform of the U.S. health care system is once more taking center stage.

I recently represented the sterile compounding pharmacy industry at the Alliance for Patient Access (AfPA) Policy Forum on this issue. My sincere appreciation goes out to the AfPA for planning and executing the meeting and to Drs. David Kloth (Connecticut Pain Care) and Joshua Prager (Center for Rehabilitation of Pain Syndromes and California Pain Medicine Centers) for their leadership on this issue.

Over the course of the two-day forum, leading physicians in pain management and Medicare policy experts (who are also schooled in the detail and history of payment and coverage regulation), discussed the merits of taking a legislative path and negotiating through the coverage, coding and payment web.

Attorneys Paul Radensky and Paul Rudolf of the Arnold & Porter Washington, D.C. office are working with the group in three key areas: drug payment, administrative hassles, and pump refill and electronic analysis/programming code valuation.

The current objectives are:

Drug payment: Seek the development of a fee schedule to replace invoice-based pricing with fair payment to reflect costs for acquiring, handling and maintaining drugs. Pursuing regional fee schedules is a near-term objective under consideration, while longer-term, seeking CMS adoption of a national method for a fee schedule is being examined by the group.

Administrative hassles: Address significant cost and time issues with regional MACs handling the claims.

Pump refill and electronic analysis/programming code valuation: Look at the distribution for these codes and model indirect/direct ratios and practice cost indices and the impact of different specialty mixes. Radensky and Rudolf also are working to confirm current specialty crosswalk for these services with CMS. In addition, they are investigating the status and scope of the AMA�s survey of interventional pain indirect expense and considering the impact on the timing and scope of pursuing the issue with CMS. This will be useful in considering whether new codes may be required.

Join me, please, in making our collective voice heard! Register your concern for patients by sending an email to stoppain@hartleymedical.com today. We will keep you informed on this issue. We’ll also let you know how you can join Hartley Medical in our effort to ensure adequate reimbursement for physicians that preserves this treatment option for patients.

At Hartley Medical, we strive to maintain the optimal environment for compounding sterile drugs. Long before the United States Pharmacopeia (USP) Chapter 797�s guidelines for sterile compounding were introduced, we initiated an effective environmental monitoring program that incorporates advanced technology.

It is important to understand value of Hartley Medical’s equipment associated with exceeding USP 797 regulations for the elimination of bacteria and inanimate microbial or inanimate particles for appropriate sterile compounding. USP 797 requires that pharmacies compound sterile products within a Class 100 environment. Classification 100 is an old standard of the Federal 209-E, stating air classifications of Class 1 through 1,000,000, calibrations and defining air cleanliness. Therefore, a Class 100 Laminar Air Flow Workbench (LAFW / IV Hoods) is defined as providing air quality with no more than a hundred 0.5 micron-size particles to be contained within a cubic foot of air. The ISO 9000 Publication has now revised those past standards, defining the new classification of ISO with a number between 1 and 10. The ISO standards stipulate that Class 100 filtration devices represent an ISO classification of 5. With regard to ISO 5 classification, the concentration of air particles cannot exceed 3,520 per cubic meter. The two standards are differentiated through conversion of particle content to the metric system.

At Hartley Medical, we utilize Class 10 IV hoods that deliver a filtration of no more than 10 particles per cubic foot. The average compounding pharmacy is utilizing Class 100 LAFW/IV Hoods. Our greater filtration capacity provides an optimum environment for sterile compounding and exceeds federal standards.

In addition, our IV hoods are tested for microbial and non-viable air particles. USP 797 states that sterile compounding pharmacies will certify the IV hoods every six months. However, at Hartley Medical we certify our IV hoods every 120 days to closely monitor their function and detect any problems in filtration sooner. For microbial testing we employ a Bioscience SAS 100 Air Sampler. This device will draw 1,000 liters of air across a growth medium plate, detecting the microbial load that could exist in the IV hood area.

At Hartley Medical, we are ahead of both federal and state guidelines affecting sterile compounding. Please review the Polyanalgesic Consensus Conference publication discussing pharmacy compounding and compare its standards with those of Hartley Medical.

Bupivacaine is a local and central nervous system anesthetic drug originally discovered in 1957 along with mepivacaine. German chemical engineers isolated bupivacaine from a compound called cinchocaine. Bupivacaine, which has a unique structural design, produces nerve blocks for up to eight hours and is considered a second-line drug for the treatment of pain by the Polyanalgesic Consensus Conference. This drug is often combined with opioid analgesics and, in some cases, is administered as the sole agent for the relief of neuropathic pain. When combined with other drugs such as hydromorphone, morphine, fentanyl or sufentanil there was no drug induced toxicity or complications observed.

Key Studies Establish Stability
Many long-term studies have been performed regarding intrathecal administration of bupivacaine with clonidine or analgesics for the relief of pain. One particular study, again by Lawrence Trissel[1], showed stability of low and high-dose concentrations of morphine sulfate with bupivacaine when packaged in plastic syringes. The study looked at morphine, 5 mg/ml in combination with bupivacaine hydrochloride, 2.5 mg/ml in sodium chloride 0.9%. The findings indicated that there was no loss of morphine or bupivacaine concentrations in the samples that were stored at 4�C and 23�C for 60 days.

Additionally, Trissel studied the stability of morphine sulfate, 50 mg/ml and bupivacaine, 25 mg/ml also stored at 4�C and 23�C. This study also concluded that there was no loss of potency for up to 60 days. In another study by K.R.Hildebrand[2] et. al., the objective was to show that the drug was effective for relief of pain when administered through an implantable drug delivery device. In this particular study, commercially available bupivacaine at 7.5 mg/ml was incubated at 37�C for 12 weeks within an implantable infusion device. It was revealed that concentrations remained greater than 96 percent in the implantable drug delivery systems. Stability of bupivacaine is well documented in many other publications.

A December 2004 article in the Journal of Pain and Symptom Management showed bupivacaine hydrochloride, 20 mg/ml, morphine sulfate, 50mg/ml and clonidine, 2mg/ml to be stable within an implantable infusion device for 90 days.

Recommended Dosing
At Hartley Medical, we recommend that the starting dose of bupivacaine be maxed out at approximately 1 to 5 milligrams per day. The upper doses of bupivacaine should not exceed 15 milligrams per day. However, various pain physicians in the western United States have utilized bupivacaine for the treatment of both cancer and non-cancer pain, with doses ranging from 30 to 40 mg/day.

Pivotal Role as Anti-Microbial
A very significant study of bupivacaine was published by Per H. Rosenberg, M.D., and Olli V. Renkonen[3]. The authors examined the anti-microbial activity of bupivacaine and morphine against 10 strains of bacteria. Bupivacaine was studied with various microorganisms, in particular E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus and epidermis. The concentrations of bupivacaine examined were 0.5 mg/ml and 1.25, 2.5, and 5 mg/ml. Bupivacaine in concentrations of 2.5 mg/ml inhibited growth of Staph. epidermis strain and Staph. pyogenes as well as Streptococcus pneumonia. Morphine showed no growth-inhibiting activity against bacteria.

The study�s bottom line is that bupivacaine spurs anti-bacterial activity against common pathogens. More significantly, bupivacaine has specific inhibitory effects on Staphylococcus aureus and Staphylococcus epidermis commonly found on human skin. Bupivacaine has a maximum solubility at 40 mg/ml at room temperature. However, bupivacaine�s solubility increases with temperature; therefore, bupivacaine in concentrations exceeding 40 mg/ml can be stable in an implantable infusion device at 37�C. However, bupivacaine 40mg/ml stability may be compromised when combined with other drugs within an implantable infusion device.