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Editorial: Depyrogenation Methods

This week, we will begin a new series on some technical issues related to nonsterile and sterile compounding. Many of the topics to be covered were mentioned in previous newsletters on the topic of '483 inspection reports resulting from FDA inspections of compounding pharmacies. The first will discuss the resources and documentation for depyrogenation methods.

Pyrogens generally come from one of three sources: water used as a solvent (the main source), chemicals used in the preparation of the solution, or from coming into contact with containers or during packaging, storage, or administration.

Because pyrogens, or bacterial endotoxins, are soluble in water, sterilization with moist heat under pressure nor filtration through sterilizing filters eliminates them. It is impractical and almost impossible to remove pyrogens without adversely affecting a finished drug product. The emphasis, therefore, is on preventing the introduction or development of pyrogens in all aspects of the compounding and processing of a compounded preparation.

Depyrogenation methods include the following:

• Heating at 250�C for 45 minutes to 1 hour; also 180�C for 4 hours (e.g., metal and glass containers)
• Careful heating with dilute alkali or dilute acid
• Oxidation with peroxides and permanganates
• Adsorption using activated charcoal
• Size exclusion filtration/chromatography
• Reverse osmosis
• Filtration with a positively charged, endotoxin-retaining 0.22-micron or better filter (since endotoxins are negatively charged)
• Washing with detergent and rinsing with SWFI or WFI prior to sterilization (e.g., plastics, glassware)

Traditionally, depyrogenation is first thought of as the dry-heat incineration of endotoxins from materials able to withstand the protracted dry-heat cycle needed to destroy the lipopolysaccharide molecule. Alternatively, the wash/rinse removal of endotoxins from items such as stoppers and plastic components and alternative vial closures comes readily to mind when heat treatment is not an option.

References and Excerpts

1. The oldest and simplest method of endotoxin removal from solid surfaces is rinsing with a nonpyrogenic solvent, usually water for injection with subsequent sterilization or sterile water for injection. Low levels of surface endotoxin contamination can be effectively removed from glassware, device components, and stoppers, for example, with an appropriate washing procedure. Rinse water can be monitored throughout the process with the LAL test to validate/verify endotoxin removal. An example of such a validation process for large-volume parenteral glass containers has been described by Feldstine et al. [1. Williams KL. Endotoxins: Pyrogens, LAL Testing and Depyrogenation. 2nd ed. New York, NY: Marcel Dekker, Inc., 2001.] [2. Technical Report No. 7 Depyrogenation. Bethesda, MD: Parenteral Drug Association; 1985.]
   
   
2. Pyrogens can be eliminated from metal and glass containers by dry heat. When this is not practical, owing to the size of the containers or the nonavailability of proper dry-heat equipment, pyrogens can be eliminated by rinsing the containers well with pyrogen-free Water for Injection; the pyrogens, being water-soluble, are removed by repeated rinsings. [Turco S. Sterile Dosage Forms: Their Preparation and Clinical Application. 4th ed. Philadelphia, PA: Lea & Febiger; 1994.]
   
   
3. When it is not practical to eliminate pyrogens with dry heat, the equipment must be thoroughly washed with Water for Injection. [Turco S. Sterile Dosage Forms: Their Preparation and Clinical Application. 4th ed. Philadelphia, PA: Lea & Febiger; 1994.]
   
   
4. Dry heat is the normal method of depyrogenation of equipment and containers but, where dry heating is not feasible, cleaning with pyrogen-free water is used since most endotoxins are water soluble. [Groves MJ. Parenteral Technology Manual: An Introduction to Formulation and Production Aspects of Parenteral Products. Prairie View, IL: Interpharm Press Inc.; 1985.]
   
   
5. It has been claimed that thorough washing with detergent will render glassware pyrogen free, if subsequently rinsed thoroughly with pyrogen-free water. Rubber stoppers cannot withstand pyrogen-destructive temperatures, so reliance must be on an effective sequence of washing, thorough rinsing with WFI, prompt sterilization, and protective storage to ensure adequate pyrogen control. [Akers MJ. Parenteral preparations. In: Remington: The Science and Practice of Pharmacy. 22nd ed., Philadelphia, PA: Pharmaceutical Press; 2013.
   
   
6. Validation of a depyrogenation method can be accomplished through the use of the LAL test. [Akers MJ. Sterile Drug Products: Formulation, Packaging, Manufacturing, and Quality. New York, NY: Informa Healthcare; 2010.]
   
   
7. The ultimate test on the efficiency of depyrogenation is the result obtained from endotoxin testing for the sterile preparation.

FDA Sparring with Compounding Pharmacy Over Recall
The FDA is at loggerheads with a Dallas compounding pharmacy that refuses to comply with enforcement steps. The FDA has taken the unusual step of issuing a "reminder" to healthcare providers not to administer any sterile drugs made and distributed by NuVision Pharmacy. The agency had requested an immediate recall of all of its sterile products. The compounder, however, issued a statement on its website maintaining that it does not qualify as a drug manufacturer and "current state laws do not require compounding pharmacies to follow (FDA) standards for manufacturing." In addition, NuVision added that it is not issuing a recall for all products, and the FDA maintains it cannot require the compounder to do so.

NuVision did recall some methylcobalamin injection in April and noted that it had received reports of fever, flu-like symptoms, and injection-site pain with one of these products. "The agency is not aware of any adverse event reports associated with other sterile products from NuVision," the FDA said.
http://www.pharmalive.com/fda-spars-with-recalcitrant-compounding-pharmacy-over-a-recall
http://www.medpagetoday.com/Washington-Watch/FDAGeneral/41040

State Inspection Closes Two Compounding Pharmacies in Massachusetts
Compounding pharmacies in Quincy and Norwood were closed after a surprise state inspection found several alleged violations. "During the inspection, the pharmacy was observed to be non-compliant with Board regulations, including requirements pertaining to verifying prescriptions, drug inventories, expired medications and sterile compounding." Subsequently, The Board of Registration in Pharmacy ordered the pharmacy to halt all pharmacy operations.

A cease-and-desist notice was sent to Medi-Son's sister company, CarePro (in Quincy), for assisting Medi-Son in violating the cease and desist notice. The Board of Registration also voted in July to suspend the licenses for Medi-Son, CarePro, and managers Christopher Le and Son Dinh.
http://www.bostonglobe.com/2013/08/20/compounding-pharmacies-quincy-norwood-closed-after-surprise-state-inspection/0bZxQCjsb7vrBu8Qk8AW0I/story.html

Prefill Flush Syringes Recalled by Covidien
Covidien is recalling 14 lots of its Monoject prefill flush syringes sold in the U.S. and Bermuda, as they contained nonsterilized water which could cause life-threatening infections. In addition, some of the syringes also had mismatched caps, labels, and wrappers.
http://www.reuters.com/article/2013/08/19/us-covidien-recall-syringes-idUSBRE97I0YZ20130819

Cancer Drug Shortages Persist
The FDA has been ineffective in heading off cancer drug shortages, in part because the agency has little authority to address what causes them to occur. Lisa Kubaska, PharmD, FDA spokesperson, credited the 2012 Food and Drug Safety Innovation Act with allowing the agency to identify shortages and find temporary solutions but said on the front lines, the picture is not that rosy, although she believes the FDA is doing what it can. Many factors contributing to drug shortages are those that the agency has limited control over.
http://www.ajmc.com/publications/evidence-based-oncology/2013/2013-1-vol19-sp6/Drug-Shortages-Persist-in-Wake-of-Surveys

Eli Lilly Also Involved in Bribery Allegations in China
Eli Lilly has said it was "deeply concerned" about allegations published in a Chinese newspaper that it spent more than 30 million yuan ($4.90 million) to bribe doctors in China to prescribe the firm's medicines instead of competing products.

Eli Lilly joins GlaxoSmithKline and Novartis AG in the probes. Charges are that to hit sales at rival companies and push the company's own products, bribes and special payments of all sorts were extremely common in these companies. Also being investigated by the Health Ministry officials is Sanofi SA.
http://www.reuters.com/article/2013/08/22/elililly-china-bribery-idUSL4N0GN0JW20130822

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PCAB is proud to announce the accreditation of the following pharmacies:

Wellness Pharmacy, Birmingham, Alabama; Mary Ann Davis, RPh, mdavis@wellnesshealth.com. Re-accreditation for Sterile & Nonsterile Compounding

Dripping Springs Pharmacy, Dripping Springs, Texas; Kathryn Van Besien, PharmD, kathryn@cpdwellness.com. Initial Accreditation for Sterile & Nonsterile Compounding

McCrory's Pharmacy Inc., El Paso, Texas; Gary McCrory, RPh, gmccrory@aol.com. Initial Accreditation for Sterile & Nonsterile Compounding