Save $500K; Hacking USP

USP <800>: Looming Compliance Deadline

Less than a year away pharmacies will be expected to comply with USP’s newest standard pertaining to the handling of hazardous drugs (HDs). Is your pharmacy ready? If not, don’t start construction just yet; there’s a possibility you may not have to. First, your State Board of Pharmacy may be deciding whether they’re going to enforce or not. So that could be one way out of compliance. However, there’s another “out” so to speak; it’s built right into the standard actually.

Perform an assessment of Risk

As a part of the standard the USP has given pharmacies the chance to perform an assessment of risk for those who may be dealing with dosage forms that may not pose a significant risk:

Some dosage forms of drugs defined as hazardous may not pose a significant risk of direct occupational exposure because of their dosage formulation (e.g., tablets or capsules—solid, intact medications that are administered to patients without modifying the formulation). However, dust from tablets and capsules may present a risk of exposure by skin contact and/or inhalation. An assessment of risk may be performed for these dosage forms to determine alternative containment strategies and/or work practices. If an assessment of risk is not performed, all HDs must be handled with all containment strategies defined in this chapter.

The assessment of risk must, at a minimum, consider the following:
• Type of HD (e.g., antineoplastic, non-antineoplastic, reproductive risk only)
• Dosage form
• Risk of exposure
• Packaging
• Manipulation
If an assessment of risk approach is taken, the entity must document what alternative containment strategies and/or work practices are being employed for specific dosage forms to minimize occupational exposure. If used, the assessment of risk must
be reviewed at least every 12 months and the review documented.

I contend this could be expanded to other dosage forms as well, beyond tablets and capsules. I think the vast majority of dosage forms being manipulated in hospitals (sealed sterile containers being further diluted) could potentially be exempt if an assessment of risk is performed (this is just my opinion). I would say that the handling of bulk powders should probably be the only form we should go all out protecting our operators from; again, just my opinion. Be sure to follow whatever your local jurisdiction has adopted!

Nonetheless, I’m going to outline how to perform a risk assessment that would prove beyond the shadow of a doubt your current practices are either working (or NOT working) and more to the point, could get you on the path to potentially finding alternative containment strategies rather than building an entirely new clean room. For those of you who already have. Apologies. The money was well spent I’m sure.

Ground Rules

Let’s set some ground rules before I get into the meat and potatoes of a risk analysis. First, you should have good primary engineering controls to begin with; a biological safety cabinet (or vented isolator) is really minimum. These primary controls are the…well, they’re the primarydefense against protecting operators from contamination with hazardous drugs. So really this is a bare essential. I’m not recommending skimping on protecting operators. What I am recommending is a thorough analysis of your procedures to set a minimum standard for protecting them. Again, USP standards tend to be prescriptive in nature but with some sound scientifically backed analysis and documentation (these are KEY) of an alternative containment strategy, it’s my belief that a huge (expensive) construction project may not be necessary.

A Risk Assessment Model: Hazard Analysis and Critical Control Points (HACCP)

HACCP was originally intended for use in the food safety management system; identifying known hazards and reducing risks from occurring at specific points in the food chain. The methods used easily transfer to a pharmaceutical environment for systematically identifying, assessing and controlling risks from handling hazardous drugs.

There are 12 tasks to accomplish in order to complete an HACCP. Within these steps you’ll find the seven principles of HACCP as well. The seven principles are the underlying guidelines for preventing known hazards and to reduce the risk of occurrence at any point in a process.

1. Establish HACCP team – form a team that is made up of people from a wide range of disciplines
2. Describe the product (you’re trying to protect operators from) – what HD are you protecting operators from? What are the known hazardous of this drug?
3. Identify the product’s intended use – injectable vs oral dosage form
4. Draw up the process flowchart – from the point of receiving into pharmacy from wholesaler
5. On-Site confirmation of flowchart – have team walk through the process step-by-step to verify nothing is missing from flowchart
6. Conduct hazard analysis (Principle 1) – of the 3 hazards (biological, chemical and physical) we’re dealing with a chemical
   1. Identify hazard: chemical
   2. Hazard analysis: These HDs have already been identified by NIOSH as substances that pose a substantial risk to humans
7. Determine the Critical Control Points (CCPs) – see diagram (Principle 2); USP 800 has basically already identified these (but may not be all inclusive – you should perform this using the diagram below)
   1. Receipt of HD
   2. Storage of HD
   3. Handling of (compounding; sterile and non-sterile) HD
   4. Disposal of HD (I’m adding this as it also seems to me like an obvious CCP)
8. Establish target levels and critical limits (Principle 3) – It’s critical to establish critical limits and target levels as this will be how you’ll know whether your process to prevent exposure is actually working. While USP suggests medical surveillance and wipe sampling, they have some major shortcomings. There have been no real minimum levels of surface contamination set for any HDs that corresponds to being a true hazard. Is a kilo of free cyclophosphamide powder on a countertop hazardous? Probably. How about 1 mg, 10 mg, 100 mg? USP 800 identifies surface cyclophosphamide levels >1.00 ng/cm2 as a level that was taken up by workers. However, was there any correlation to actual disease or illness as a result? I DO think it’s a good idea to have some baseline medical surveillance for employees and follow up if a suspected exposure or a change in health status occurs. But I also think further studies need to be done using this data that we’re collecting from medical surveillance to draw REAL (scientifically backed) conclusions. My final point is that there aren’t too many guidelines we can draw from the literature for setting limits NOR is there many available methods for collection and analysis of residues for all of the HDs that we compound with. Unfortunately, you’ll have to figure this out for yourself using the limited tools we currently have at our disposal. But all is not lost in a previous post I suggested the use of Total Organic Carbon (TOC) analysis to verify your surfaces were properly being cleaned, decontaminated and disinfected. By using TOC analysis you can “validate” your cleaning procedure (design experiment and perform at least 3 times to verify you’re able to completely deactivate and remove HDs from surfaces – and document REALLY well).
9. Establish a system to monitor the CCPs (Principle 4) – establish procedures for each of the 4 CCPs above designed specifically to prevent exposure
10. Establish a Corrective Action Plan for each CCP (Principle 5) – if above procedure was not followed or something occurred preventing the procedure from being properly carried out there needs to be a corrective action plan in place to ensure that the CCP is once again under control.
11. Establish a system to verify that the HACCP system is working effectively (Principle 6) – once the HACCP is in place and all CCP have been validated for effectiveness the system must be routinely verified and reviewed at regular intervals.
12. Establish a record-keeping system (Principle 7)

Below is an example flow diagram to illustrate the seven principles used in identifying Critical Control Points (points in a process that are considered critical to control to prevent a contamination). Within HACCP there are 7 principles:

After you’ve performed the basic steps of the HACCP, you’ll need to document your process. I’ve made a very simple template to get you started on this process. I recommend customizing this completely to suit your needs.

HACCP template

References:

1. Quality Risk Management in the FDA regulated industry by Jose Rodriguez Perez
2. http://www.fao.org/docrep/005/y1579e/y1579e03.htm

About the author:

Seth DePasquale is a pharmacist and co-owner of BET Pharm, LLC in Lexington, KY; a compounding pharmacy specializing in long-acting injectable hormone formulations for equine reproduction. Seth is a 2002 graduate of Albany College of Pharmacy in Albany, NY and is a Registered Pharmacist in New York, Kentucky, Michigan, Oklahoma, Texas, West Virginia, Virginia, Alabama, Tennessee, Mississippi, Arkansas, Nebraska, Louisiana and Oregon.