Sunday, August 30, 2009

Voltammetric determination of vitamins in a pharmaceutical formulation

Direct current polarography and differential pulse polarographic methods have been developed for the qualitative as well as quantitative analysis of vitamin B1, B2 and B6. Thiamin (Vitamin B1) produced a well-defined wave in 0.1 M KCl at pH 5.2 with E1/2=−1.2 V and Ep=−1.22 V versus saturated calomal electrode (SCE). Riboflavin (Vitamin B2) gave two distinct waves in Britton Robinson buffer at pH 1.8 with E1/2 VALUES=−0.13 and −0.34 V versus SCE and at pH 6.5 with E1/2=−1.10 V and Ep=−1.2 V versus SCE. Pyridoxin (Vitamin B6) produced a well-defined wave in Britton Robinson buffer at pH 6.5 with E1/2=−1.7 V and Ep=−1.68 V versus SCE. All the three Vitamins under study are reversibly reduced at the electrode surface. The number of electrons involved in the electrode process for vitamin B1 and B6 is one in each case where as for the two waves of B2 it is one and two, respectively. This has been confirmed by the measurement of E3/4E1/4 values and also from the log plot slopes for the reduction waves. The wave height of polarogram was found to be proportional to the vitamin concentration. The developed methods have been standardised for the determination of these compounds in pharmaceutical formulation. The concentration of Vitamin B1, B2 and B6 are found to be 9.96, 9.92 and 3.01 mg, respectively in 240 mg of capsule powder of a standard company (name has not been disclosed due to secrecy purpose). The results have been found to be in excellent agreement to that claimed by the manufacturer. The observed data has been subjected to statistical analysis, which revealed high reliability and precision.

Author Keywords: Vitamins; Thiamin; Riboflavin; Pyridoxin; DCP; DPP; Pharmaceutical formulation

Processes of making and using pharmaceutical formulations of antineoplastic agents

This application is a divisional application of U.S. Ser. No. 10/371,808 filed Feb. 21, 2003, now allowed, which claims the benefit of U.S. Ser. No. 60/359,198 filed Feb. 22, 2002, the entirety of which are incorporated by reference as if set forth fully herein.


The present invention pertains to pharmaceutical formulations comprising antineoplastic agents, such as Temozolomide, and dissolution enhancing agents.


Antineoplastic agents are useful in cancer therapies against a wide array of cancer and other diseases. Temozolomide is one such antineoplastic agent. U.S. Pat. No. 6,096,759 lists a variety of antineoplastic agents including Temozolomide, the disclosure of which is incorporated herein by reference.

Temozolomide is known for its anti-tumor effects. For example, one study showed that clinical responses were achieved in 17% of patients having advanced melanoma (Newlands E S, et al. Br J Cancer 65 (2) 287-2981 (1992)). In another study, a clinical response was achieved in 21% of patients with advanced melanoma (Journal of Clinical Oncology, 13(4) 910-913 (1995)). Treatment of gliomas in adults with Temozolomide is also known (Eur. J. Cancer 29A 940 (1993)). Treatment of the following cancers in adults with Temozolomide has also been disclosed: metastatic melanoma; malignant melanoma, high grade glioma, glioblastoma and other brain cancers; lung cancer; breast cancer; testicular cancer; colon and rectal cancers; carcinomas; sarcomas; lymphomas; leukemias; anaplastic astrocytoma; and mycosis fungoides.

Temozolomide is a water-insoluble compound. Temozolomide has been administered in patients as micronized suspensions, as disclosed in U.S. Pat. No. 6,251,886. However, suspension formulations are not desirable because they may lead to clogged veins.

Storage of pharmaceutical and biological agents, especially antineoplastic agents, as a frozen solution can cause the active ingredient therein to rapidly deteriorate.

Lyophilization, also known as freeze-drying, is a process whereby water is sublimed from a composition after it is frozen. In this process, pharmaceutical and biological agents that are relatively unstable in an aqueous solution over a period of time can be placed into dosage containers in an easily processed liquid state, dried without the use of damaging heat and stored in a dried state for extended periods. Most pharmaceutical and biological agents, including antineoplastic agents, require additional ingredients to protect the active ingredient during lyophilization. In addition, it can be difficult to reconstitute a lyophilized antineoplastic agent into an aqueous solution.

Accordingly there is an increased need for formulations containing antineoplastic agents, such as Temozolomide, which are water soluble, stable and/or suitable for lyophilization, long term storage and reconstitution of the lyophilized formulation into an aqueous solution.

Furthermore, there is an increased need for administering to a patient an antineoplastic agent, such as Temozolomide, as a water soluble and stable formulation.


This invention relates to pharmaceutical formulations comprising at least one antineoplastic agent, processes of making the same, processes of lyophilization of the pharmaceutical formulations, lyophilized powders and articles of manufacture thereof, pharmaceutical formulations comprising the lyophilized powder reconstituted in at least one aqueous diluent, and processes of treating or preventing diseases comprising administering the pharmaceutical formulation to an animal in need thereof.

One aspect of the invention relates to a pharmaceutical formulation comprising at least one antineoplastic agent or a pharmaceutically acceptable salt thereof, at least one aqueous diluent, and at least one dissolution enhancing agent sufficient to substantially dissolve said antineoplastic agent(s), wherein said dissolution enhancing agent is urea, L-histidine, L-threonine, L-asparagine, L-serine, L-glutamine or mixtures thereof.

Another aspect of the invention relates to a process for making the pharmaceutical formulation of the invention. This process comprises the steps of dissolving at least one dissolution enhancing agent in at least one aqueous diluent, and adding at least one antineoplastic agent or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to a lyophilized powder produced by lyophilization of the pharmaceutical formulation of the invention.

Another aspect of the invention relates to an article of manufacture comprising a container containing the lyophilized powder of the invention.

Another aspect of the invention relates to a pharmaceutical formulation suitable for administration to a patient, wherein the formulation is prepared by reconstituting (resolubilizing) the lyophilized powder of the invention in a volume of water or other aqueous diluent.

Another aspect of the invention relates to a process for treating or preventing diseases in patients comprising administering a therapeutically effective amount of the pharmaceutical formulation of the invention to a patient in need thereof.

Other aspects of this invention relate to and disclose pharmaceutical formulations of Temozolomide, a process of making the same, a lyophilized powder of said formulation and articles of manufacture thereof, a pharmaceutical formulation comprising the lyophilized powder reconstituted in water or other aqueous diluents, and a process of treating or preventing diseases (such as, for example, cancer) comprising administering the pharmaceutical formulation to a patient in need thereof.

How to use Glycerin Suppositories:

Use Glycerin Suppositories as directed by your doctor. Check the label on the medicine for exact dosing instructions.

  • Wash your hands before and after using Glycerin Suppositories.
  • If the suppository is too soft to use, put it in the refrigerator for about 15 minutes or run cold water over it. Then remove the wrapper and moisten the suppository with cool water. Lie down on your side. Insert the pointed end of the suppository into the rectum, then use your finger to push it in completely.
  • If you miss a dose of Glycerin Suppositories, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses in the same day, unless directed otherwise by your doctor.

Ask your health care provider any questions you may have about how to use Glycerin Suppositories.

Important safety information:

  • Glycerin Suppositories are for rectal use only.
  • Do not use Glycerin Suppositories for longer than 1 week without checking with your doctor.
  • Do not take Glycerin Suppositories without talking to your doctor if you have had a sudden change in bowel movements lasting longer than 2 weeks or you are experiencing nausea, vomiting, or stomach pain.
  • Different products may have different dosing instructions for CHILDREN on the package labeling. Follow the dosing instructions provided on the package labeling or by your doctor. If you are unsure of what dose to give a child, check with your doctor.
  • PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Glycerin Suppositories, discuss with your doctor the benefits and risks of using Glycerin Suppositories during pregnancy. It is unknown if Glycerin Suppositories are excreted in breast milk. If you are or will be breast-feeding while you are using Glycerin Suppositories, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Glycerin Suppositories:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Anal irritation; burning sensation; diarrhea; gas; nausea; stomach cramps.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); rectal bleeding.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center (, or emergency room immediately. Symptoms may include diarrhea; stomach cramps.

Proper storage of Glycerin Suppositories:

Store Glycerin Suppositories at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Glycerin Suppositories out of the reach of children and away from pets.

General information:

  • If you have any questions about Glycerin Suppositories, please talk with your doctor, pharmacist, or other health care provider.
  • Glycerin Suppositories are to be used only by the patient for whom it is prescribed. Do not share it with other people.
  • If your symptoms do not improve or if they become worse, check with your doctor.

This information is a summary only. It does not contain all information about Glycerin Suppositories. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Glycerin Suppositories

Relieving occasional constipation. It may also be used for other conditions as determined by your doctor.

Glycerin Suppositories are a hyperosmotic laxative. It works by irritating the lining of the intestine and increasing the amount of fluid, making it easier for stools to pass.

Do NOT use Glycerin Suppositories if:

  • you are allergic to any ingredient in Glycerin Suppositories
  • you have a blockage in your digestive system
  • you have undiagnosed abdominal pain

Contact your doctor or health care provider right away if any of these apply to you.

Before using Glycerin Suppositories:

Some medical conditions may interact with Glycerin Suppositories. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

  • if you are pregnant, planning to become pregnant, or are breast-feeding
  • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
  • if you have allergies to medicines, foods, or other substances
  • if have appendicitis or rectal bleeding

Some MEDICINES MAY INTERACT with Glycerin Suppositories. However, no specific interactions with Glycerin Suppositories are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Glycerin Suppositories may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

Monday, August 10, 2009

Microbiological assay for ceftazidime injection

A simple, sensitive, and specific biodiffusion assay for the antibacterial ceftazidime was developed using a strain of Staphylococcus epidermidis (ATCC 12228) as the test organism. Ceftazidime was measured in powder for injection at concentrations ranging from 100 to 400 lag/mL. The calibration graph for ceftazidime was linear ([r.sup.2] =1), and the method validation showed that it was precise (relative standard deviation = 0.415) and accurate. The results obtained by biodiffusion assay were statistically calculated by linear parallel model and by means of regression analysis and were verified using analysis of variance. It was concluded that the microbiological assay is satisfactory for in vitro quantification of the antibacterial activity of ceftazidime in pharmaceuticals.

Ceftazidime is a third-generation cephalosporin that is widely used for the treatment of serious infections caused by Gram-negative bacteria, including Pseudomonas aeruginosa, especially in cystic-fibrosis patients. It is usual to administer this drug by slow intravenous infusion over 24 h. The infusion solutions are prepared in advance and stored in the pharmacy (1). The favorable properties of ceflazidime include efficient penetration of the bacterial cell wall, resistance to bacterial enzyme degradation, a high intrinsic activity against the bacterial cell targets, a broad spectrum of activity, very low toxicity, extensive tissue penetration, metabolic stability, and a low degree of serum protein binding (2).

Assays reported in the literature for determination of ceftazidime in biological fluids include high-performance liquid chromatography (HPLC; 3) and spectrophotometry using batch and flow-injection procedures. For the measurements in pharmaceuticals, several methods are reported for determination of cephalosporins, including HPLC, spectrophotometry, fluorimetry, polarography, colorimetry involving treatment with sodium cobaltinitrite, ninhydrine, molybdophosphoric acid, oxidation with Ce(IV) or Fe (III), hydroxamic acid, ammonium vanadate, iodometric titration, and spectrophotometric UV analysis (4-6).

Although the antimicrobial activity and pharmacokinetics of this drug have been widely researched, few studies in the literature relate to the development of analytical methodology for this cephalosporin. Research involving analytical methods is of basic importance to optimize its analysis in the pharmaceutical industry and to guarantee the quality of the commercialized product.

Parameters specified in assays with other cephalosporins (7) were carried through preliminary tests to standardize the conditions to be used, such as test organism, growth media, diluents, inoculum, and drug concentration. The basic requirement for a test organism is that it should be nonpathogenic, sensitive to the action of the antibiotic under assessment, and capable of rapid growth. The chemical structure of ceflazidime is represented by Figure. 1. Ceftazidime is commercialized in Brazil under the name of Ceftazidon by Ariston Quimica e Farmaceutica Ltda (SAO Paulo, Brazil) and as Fortaz by Glaxo SmithKline (SAO Paulo, Brazil). No microbiological assay for determination of ceflazidime and its formulations has been reported for laboratory quality control. This assay can reveal subtle changes not demonstrated by chemical methods, such as chemical degradation, and allows evaluation of the potency of ceftazidime, which is very important in the analysis of antibiotics.

The objective of the present study was to find a sensitive and reproducible biodiffusion assay to quantify ceftazidime in raw material and powder for injection, and to validate the method by determining the parameters of linearity, precision, and accuracy.


Ceftazidime reference substance (assigned purity 99.98%) as well as ceflazidime powder for injection were generous gifts from Ariston. Ceftazidime powder for injection was claimed to contain 1000 mg of the drug and sodium carbonate as excipient. All chemicals used were of analytical reagent grade.

Preparation of Ceftazidime Reference Substance

The standard solution in water (1 mg/mL) was diluted in potassium phosphate buffer, pH 6.0, and assayed at concentrations of 100, 200, and 400 [micro]g/mL.


Sample Preparation

Twenty samples containing ceftazidime powder for injection were weighed, and the medium weight was determined. An amount of powder equivalent to 100 mg ceftazidime was transferred to a 100 mL volumetric flask with 50 mL water and shaken. This was followed by diluting to volume with water (1000 [micro]g/mL). The dilutions were made with potassium phosphate buffer, pH 6.0, to give final concentrations of 100, 200, and 400 [micro]g/mL. This dilution procedure was performed in triplicate.

Organism and Inoculum

The culture of Staphylococcus epidermidis (ATCC 12228) stored in the freezer was cultivated on Grove Randall No. 1 agar (Merck, Darmstadt, Germany) and transferred to another Grove Randall No. 1 agar (24 h before the assay) that was kept at 35 f 2[degrees]C. The bacteria were suspended in tryptic soy broth (TSB; Sparks, MD) using a glass homogenizer. Diluted culture suspensions of 25 [ or -] 2% light transmission were obtained at 580 nm, using a suitable spectrophotometer (UV-Vis JAS.CO 7800), and a 10 mm diameter test tube of absorption cells against TSB was used as blank. Portions of 0.5 mL of the inoculated TSB were added to 100 mL Grove Randall No. 1 agar at 35 f 2[degrees]C and used as the inoculated layer.

Biodiffusion Assay

The agar was composed of 2 separate layers, and only the upper layer was inoculated; this procedure may afford greater sensitivity than a single-layer plate (8). The Grove Randall No. 2 agar (21 mL) was poured into a 100 x 20 mm Petri dish as a base layer. After solidification, 4 mL portions of inoculated Grove Randall No. 1 agar were poured onto the base layer (9). Six stainless steel cylinders of uniform size (8 od x 6 id x 10 mm high) were placed on the surface of the inoculated medium. Three alternated cylinders were filled with 200 [micro]L of the reference solutions, and the other 3 were filled with the sample solutions. After incubation (35 f 2 [degrees]C for 21 h), the zone diameters (in mm) of the growth inhibition were measured using a caliper (Starret, Chicago, IL).


The percent activity of ceftazidime in powder for injection was calculated by Hewitt equations (10). The assay was statistically calculated by linear parallel model and by means of regression analysis of variance (ANOVA).

Method Validation

The method was validated by determination of linearity, precision, and accuracy (11, 12). In order to assess the validity of the assay, the linearity was determined by using 3 doses of the reference substance and 3 doses of the sample. The calculation of regression line by the method of least squares was used. The accuracy was determined by adding known amounts of ceftazidime reference substance to the samples at the beginning of the process. Amounts of 0.1, 0.2, and 0.4 mL ceftazidime reference solution (500 [micro]g/mL) and 1.0 mL ceftazidime sample solution (1000 [micro]g/mL) were added to 10 mL volumetric flasks, respectively, [R.sub.1], [R.sub.2], and [R.sub.3]. Potassium phosphate buffer, pH 6.0, was added to give final concentrations of 105.0, 110.0, and 120.0 [micro]g/mL, respectively. The solutions were used in the biodiffusion assay described above. The percentage recovery of ceftazidime reference added was calculated using the formula proposed by AOAC (11):

R% = [([P.sub.F] - [P.sub.A])/[P.sub.P]] x 100

where [P.sub.F] = sample standard potency; [P.sub.A] = sample potency; [P.sub.P] = standard added potency. Accuracy and precision of bioassay were determined intraday and interday on the 3 different days.


Results and Discussion

In the development phase of the ceftazidime bioassay, the parameters were evaluated as test microorganism [Staphylococcus aureus (ATCC 6538) or S. epidermidis (ATCC 12228)]; culture medium; buffer pH 6.0 or 8.0; inoculum concentration 0.5, 1.0, or 2.0%; solution concentration (2.0, 4.0, 8.0 dug/mL; 8.0,12.0, 18.0 Pg/mL; and 100, 200,400 [micro]g/mL).

An experimental 3 x 3 design, using 3 dose levels for each standard and sample were used following the procedure described in the Brazilian Pharmacopoeia (7). The calculation procedure normally assumes a direct relationship between the observed zone diameter and logarithm of applied dose. There was a linear relationship between [log.sub.10] of the ceftazidime concentrations and growth inhibition zone diameter (complete diameter) for concentrations 100, 200, and 400 [micro]g/mL. The corresponding mean zone diameters for reference solutions were 12.85 [ or -] 0.04 [coefficient of variation (CV) = 0.31] for low dose, 16.83 [ or -] 0.03 (CV = 0.15) for medium dose, and 20.84 [ or -] 0.03 (CV = 0.12) for high dose (Table 1). The calibration curve for ceftazidime was constructed by plotting log of concentrations (Vg/mL) versus zone diameter (mm) and showed good linearity on the 100-400 [micro]g/mL (Figure 2). The representative linear equation for ceftazidime was y = 13.271x - 13.697, where x is a log of concentration and y is diameter zone inhibition. The coefficient of regression was [r.sup.2] = 1.0.

The experimental values obtained for determination of ceftazidime in samples are presented in Table 2. According to the Brazilian Pharmacopoeia (7), if a parallel-line model is chosen, the 2 log dose-response lines of the preparation to be examined and the reference preparations must be parallel, and they must be linear over the range of doses used in the calculation. These conditions must be verified by validity tests for a given probability, usually P = 0.05. The assays were validated by means of the ANOVA, as described in these official codes. There are no deviations from parallelism and linearity with results obtained here (P <>

The precision and accuracy of the assay were also demonstrated. Precision is usually expressed as the variance, relative standard deviation (RSD), or CV% of a series of measurements (13). The results obtained on different days showed a CV of 0.42 for powder for injection (Table 2). The accuracy is shown by the agreement between the accepted value and the value found to be 98.7% for powder for injection (Table 3).

The quantification of antibiotic components by chemical methods such as HPLC and UV spectrophotometry, although precise, cannot provide a true indication of biological activity. Attempts to correlate antibiotic bioassay results with those from chemical methods have proved disappointing. Therefore, bioassays continue to play an essential role in manufacturing and quality control of antibiotic medicines, and still demand considerable skill and expertise to ensure success. Although the biological assays have a high variability, the analysis of the obtained results demonstrated that the proposed method might be very useful for determination of this drug in pharmaceutical dosage forms.


The results indicated that the biodiffusion assay demonstrated good linearity, precision, and accuracy at concentrations ranging from 100 to 400 [micro]g/mL; therefore, it is an acceptable alternative method for the routine quality control of ceftazidime in raw materials and medicines. The method uses simple reagents, with minimum sample preparation procedures, encouraging its application in routine analysis.


We are grateful to Ariston for providing ceftazidime standard and powder for injection. This work was supported by CNPq-Brazil program and PACD-FCF-UNESP.

Received March 7, 2007. Accepted by Aft May 11, 2007.


(1) Arsene, M., Favetta, E, Favier, B., & Bureau, J. (2002) J. Clin. Pharm. Ther. 27,205-209

(2) Myers, C.M., & Blumer, J.L. (1983) Antimicrob. Agents Chemother. 24,343-346

(3) Samanidou, V.F., Hapeshi, E.A., & Papadoyannis, I.N. (2003) J. Chromatogr. B 788, 147-158

(4) Jamieson, C.E., Lambert, P.A., & Simpson, I.N. (2003) Antimicrob. Agents Chemother. 47,2615-2618

(5) Martinez, L.G, Falco, E.C., & Cabeza, A.S. (2002) J. Pharm. Biomed. Anal. 29,405-423

(6) Salem, H., & Askal, H. (2002) J. Pharm. Biomed. Anal. 29, 347-354

Static Control Avoids Cleanroom Contamination


It was in 600BC that the philosopher and mathematician Thales of Miletus first described rubbing amber on the fur of a cat and consequently being able to pick up feathers. This is the first known account of the natural force of static electricity and the word electrostatic, meaning ‘electricity at rest ‘, was introduced.

What is Static Electricity?

When a material holds a net electrical charge, either positive or negative, it is said to have a static charge. In many cases this charge will decrease slowly with time, the actual length of time being dependent on the resistance of the material. For practical purposes, the two extreme examples can be taken as plastics and metal. Plastics generally have high resistivities, allowing them to maintain static charges for long periods. On the other hand, metals have low resistances and an earthed metal object will hold its charge for only a very short period of time. At rest, static charge poses a potential contamination problem. Once a surface is charged, it will attract and hold small particles in the air having an opposite electrical charge.

Static causes problems in many manufacturing environments and even in the most stringent cleanrooms, static charge attracts particulates from people, processes and equipment. It is important that appropriate measures are taken to ensure that static is kept to a minimum, if not completely eliminated.

Controlling Static in the Cleanroom

The control of static is a major issue within cleanroom environments. In the electronics industry for example, voltages as low as 5 volts can cause catastrophic failure of components, or worse, latent damage which results in field failure. This can be very costly in terms of repair and manufacturers’ reputations.

The problem is predominantly addressed by the use of conductive or static dissipative materials in conjunction with ionisation. Ionisation inhibits the build up of static charges by delivering balanced ionised air to the target surfaces. This, in turn, prevents electrostatic discharges (ESD) and the electrostatic attraction of airborne particles. If static is not controlled, it results in contamination and damage to components, which may include semiconductors, PCB's, medical devices and thin film products directly, as well as interfering with the operation of vital production equipment.

It’s not just electronics cleanrooms that suffers from static. Sovrin Plastics, one of the UK’s leading plastics injection moulders has introduced stringent static control technology from Meech International to ensure that all its products reach the strict quality standards demanded by its customers around the world.

Sovrin Plastics Control Cleanroom Static

Sovrin Plastics, based in Slough, has been established for more than 30 years. The company has extensive experience of technical tool making, moulding, production and assembly work.

The impressive 6500 sq m site houses six Class 7 (10,000) cleanrooms (1600sq m), technical plastic injection moulding and state-of-the-art CAD/CAM and CNC tooling divisions that enables Sovrin to offer a complete design and manufacturing package for cost-effective, quality engineered solutions in plastic injection moulding.

Over the years, the company has seen its market share grow substantially with many new opportunities. One of these was the supply of medical and pharmaceutical products for the Japanese market. This new project required Sovrin to achieve even higher quality standards than were already being maintained throughout the company.

The challenges posed by opening up this new market demanded that Sovrin look afresh at its total production and assembly processes to create products that would pass the most rigorous inspection under magnification.

Sovrin’s products are manufactured and assembled in Class 10,000 cleanrooms, but even in these conditions particles, for example skin cells and facial hair, can be deposited. The plastic injection process that moulds the products creates a static charge on the items and this attracts any particles that are present, which then cling to the plastic surface. In order to reduce particulate contamination to the lowest possible level Sovrin elected to implement a complete static control policy to the production process.

One of Meech’s team of technical advisors visited the plant to fully understand the issues and recommend the most appropriate solutions. The phased implementation included the provision of a Meech Series 200 ionising blower positioned over each conveyor belt to remove static charge from the moulded parts as they are ejected from the moulds.

Meech 200 Series ionising blowers have been specifically designed to generate very large quantities of both positive and negative ions to give fast and effective control of static charge and their “whisper” quiet operation makes them ideal in the cleanroom environment. The Meech overhead blowers installed at Sovrin provides excellent workstation coverage with automatic ion balance. They provide very rapid decay times and are both easy to clean and maintain with replaceable titanium emitters. Visual and audible alarms warns if the pins are dirty or the ions are out of balance. Automatic shutdown options are also included.

Once the parts are ejected from the mould, the conveyor then deposits them into stainless steel containers that are lined with anti-static polythene bags. Each bag is sealed inside another bag for transportation to the assembly facility. Assembly work is carried out in Class 10,000 cleanroom conditions but the possible threat of particulate contamination is significantly reduced by the use of Meech bench mounted ion nozzles. These are positioned to blow ionised air across the products to neutralise any static electric charge. Any displaced particles are trapped on tacky mats placed both on the benches themselves and on the floor. These mats are changed every two hours.

Meech 271 Flexible Ion Nozzles are compact, hands free ionisers designed specifically for assembly and cleaning tasks. Their exceptionally quiet operation makes them ideal for bench-top use and they are both easy and safe to use. With low air consumption, rapid decay times and replaceable titanium emitters, the Flexible Ion Nozzles are both cost-effective and easy to maintain.

The result of the implementation of these static control solutions means that Sovrin are now answering the quality requirements of the strict Japanese marketplace.

“Contamination will always be an concern, ” says Paul Basten, Sovrin’s Production Manager, Cleanrooms. “However, being able to call on the expertise at Meech International, means we are confident that any issues can be overcome. We have been impressed with their knowledge of static and how it affects our industry and see them as partners when integrating static control solutions.”

As business grows for Sovrin Plastics, they are installing new injecting moulding equipment for a major pharmaceutical project and Meech once again will be their partner of choice.


There is no doubt that static in cleanrooms is a major issue. However, by implementing a planned and structured static control strategy such as that provided by Meech, the harmful effects can be kept to a minimum with both product integrity and company reputations being maintained. Furthermore, the resulting increased productivity, fewer rejects and higher quality levels will inevitably enhance profitability.

Sunday, August 9, 2009

Compounding sterile preparations: Onus or opportunity?

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Compounding pharmacies, equipment suppliers, and educators are all working to prove that USP <797> compliance is an attainable goal.

By Bruce Flickinger

Early in her career, Mary Monk-Tutor, PhD, spent many years as a home infusion pharmacist and for 12 years was a Joint Commission Home Care Surveyor. She remembers the time when home care patients were trained to mix total parenteral nutrition (TPN) formulations in their kitchens, and when nurses in hospitals compounded intravenous solutions on countertops. “We did this in the industry for years without infectious complications,” she says. “Obviously, these are not the safest or most appropriate environments, but it does show that it is possible to prepare at least low volumes of CSPs in uncontrolled environments without contamination.”

Things have changed in the past 20 years. Although avoiding contamination may be possible in such uncontrolled conditions, nobody now would admit to mixing intravenous and other sterile preparations on an open countertop. Doing so could cost a pharmacist his license and his livelihood, not to mention potentially compromise the safety of his patients and employees. Expectations for the handling and disbursement of compounded sterile preparations (CSPs)–loosely defined as manufacturer-supplied medicines (high-risk compounding can now involve non-manufacturer-supplied materials such as non-sterile bulk chemicals) that need to be mixed or modified by a pharmacist for patient use–have risen steadily among consumers, practitioners, and regulatory bodies. Standards for sterility and safety now have been codified in USP Chapter <797>, a federally enforceable standard introduced in 2004 and published in revised and updated form just this month.

Monk-Tutor, who is now professor of pharmacy administration and director of assessment with the McWhorter School of Pharmacy at Samford University (Homewood, AL), is among industry observers who say USP <797> is a long time in coming but still has a long way to go in terms of even, effective implementation. The standard, formally titled “USP General Chapter <797> Pharmaceutical Compounding–Sterile Preparations,” details the way sterile and high-risk pharmaceutical products should be compounded to optimally protect the safety and health of both patients and workers. It is incorporated to varying degrees in pharmacy accreditation programs and by individual state boards of pharmacy.

Like any federal mandate worth its salt, USP <797> initially prompted apprehension and procrastination in the pharmacy compounding industry, responses that have proved largely unwarranted and are for the most part dissipating. “While USP requirements are likely to become more stringent over time, they should be achievable for those organizations that have already put basic guidelines in place for compounding sterile preparations,” Monk-Tutor says.

In the wake of earlier consternation about USP <797>, two realities have emerged. The first is that the standard makes a clear demarcation between those pharmacies that want to do sterile compounding and those that do not. It is simply and primarily a business decision, one that expands the reach of care provided to patients but that requires a significant investment in training and infrastructure. The second is that education and training in sterile compounding needs to improve for those who do fall under the purview of USP <797> to achieve and maintain compliance.

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Figure 1. State boards of pharmacy’s current USP <797> compliance status (direct, indirect, or no reference). Colors indicate whether the state’s pharmacy laws are harmonized with USP <797> (direct, green); include regulations for sterile compounding and/or parenteral nutrition but do not directly cite USP <797> (indirect, yellow); or currently include no regulations referencing USP <797> or sterile compounding/parenteral nutrition (no reference, red). Adapted with permission from ClinicalIQ.

Compliance clearly entails more than simply adding sterile compounding to a pharmacy’s slate of services or for the pharmacy to continue to compound CSPs the way it did five or 10 years ago. “Sterile compounding is a complex practice; it is not a simple matter to add sterile compounding to a hospital or community practice that dispenses manufactured products and compounds non-sterile dosage forms,” says Timothy McPherson, PhD, associate professor of pharmaceutical sciences in the School of Pharmacy at Southern Illinois University Edwardsville. “Rather, complying with USP <797> becomes a full-time, resource-intense commitment.

“I’ve spent some time with one pharmacy in the Midwest that specialized in non-sterile compounding for both humans and animals,” McPherson offers as an example. “A decision was made to add sterile product compounding, so they expanded their facility and added a state-of the-art cleanroom suite. They added a partner pharmacist to be in charge of the sterile compounding business, including all QC. I don’t see how a single pharmacist could reasonably handle the responsibility for both parts of this practice.”

Taking up the challenge

The independent community pharmacist is one of several players feeling the impact of USP <797>. Pharmacy compounding is a diverse practice that also encompasses hospital pharmacies, chain pharmacies, home health-care pharmacies, and specialty infusion companies, among others. Uptake of USP <797> varies among these establishments. Some of the best facilities in terms of compliance and overall quality practice are in community and specialty pharmacies “because they can implement changes much faster than hospitals can, provided they have budgets to work with,” says Loyd Allen, Jr., PhD, editor-in-chief of the International Journal of Pharmaceutical Compounding and professor emeritus of the University of Oklahoma HSC College of Pharmacy (Oklahoma City, OK).

“Some of the best facilities I have seen are in small- or medium-sized cities and even in some smaller towns. Most of the population lives in smaller cities and towns, and they require the same medical services as people in larger cities,” Allen says. Still, he notes that some pharmacists opt to forego their sterile compounding practice and focus on non-sterile compounding if it is not economically beneficial to invest in the necessary changes in their pharmacies. Some hospitals, too, are “outsourcing more sterile compounding to specialized companies, even to local pharmacies that have the required facilities,” he says.

One snapshot of the pharmacy landscape comes from a survey conducted by McPherson and his colleagues, results of which appeared in 2006 in the Journal of the American Pharmacists Association. His team surveyed 370 pharmacies in the Midwest and found that 94 percent of them provided compounding services. However, prescriptions requiring compounding represented less than 1 percent of total prescriptions filled for the majority (58.3 percent) of respondents. Overall, only 2.3 percent of prescriptions dispensed were compounded preparations, and “only about 5 percent of our respondents offered sterile product compounding,” McPherson says.

So while there is a market for sterile compounding, McPherson senses it is being met by businesses dedicated to the practice. “Most compounders we have come into contact with avoid sterile products. They generally refer patients requesting sterile products to a qualified pharmacy in the area,” he says.

One independent pharmacy that made the decision to specialize in compounding is The Compounding Shoppe, based in Homewood, AL. The Compounding Shoppe earned the Pharmacy Compounding Accreditation Board’s (PCAB) Seal of Accreditation in September 2006 and in the process became USP <797> compliant.

“Our goal was to become PCAB-accredited, so meeting USP <797> was mandatory for achieving this,” says Scott Wepfer, a registered pharmacist and owner of The Compounding Shoppe. “The commitment for any pharmacy that wants to bring itself up to USP <797> standards is significant, both in time and money. But if you are really serious about compounding and being in business 10 years from now, then it is simply a must-do.”

Wepfer adds, “I think that with the increased regulations and the increased costs of keeping up with these regulations, we will see fewer compounders doing more compounds and doing a better job of it than today.”

The Compounding Shoppe prepares capsules, creams, ointments, gels, suppositories, enemas, oral solutions and suspensions, sublingual (under-the-tongue) tablets, nasal sprays, ear drops, transdermal pain gels, and sterile injectables. A policy and procedure manual provides step-by-step instruction on every activity performed in the compounding lab for making these dosage forms.

“Definitely, the greatest amount of time was spent in writing policies and procedures,” Wepfer says. “We purchased non-sterile and sterile policies and procedures from a vendor, then combined the two and organized them in a way that was better for us.”

Chemicals used in compounding come from FDA-inspected chemical suppliers. Upon receipt, they are placed into quarantine until their certificate of analysis is verified by a pharmacist, who then creates a barcode to place on the container and adds it into inventory, Wepfer explains. “Formulas are stored electronically in our pharmacy computer system,” he says. “When we need to compound one of the formulas, we pull up an electronic log sheet in the lab where the barcode reader and even the electronic balance are all integrated into the computer system to literally create an error-proof compounding lab.”

Any compounding that involves working with powders is done in one of four containment hoods in the lab. Policy dictates that hoods are cleaned between each project to prevent cross-contamination. For sterile compounding, a Class 10 barrier isolator, from Containment Technologies Group (CTG; Indianapolis, IN), is used. “Rather than investing in the typical cleanroom setup with open-faced hoods, we decided to invest in a sterile isolation barrier. While the upfront cost was higher, the daily consumables cost is much lower,” Wepfer says.

Clear choices

Facilities and equipment requirements, including deciding among barrier isolators, laminar airflow workbenches (LAFWs), and enclosed cleanrooms, were cause for much confusion when USP <797> was introduced. People said they were unclear about the chapter’s requirements regarding equipment, positive and negative air pressure, and the segregation of hazardous and non-hazardous drugs, among other things. And if they weren’t unclear, practitioners were concerned that the infrastructure upgrades were too expensive for the typical pharmacy. A popular position at the time was to “wait and see”–that is, to do nothing until the standard wended its way through the comment and revision process and became more widely applied by regulators.

The current set of revisions, two years in the making and incorporating more than 500 comments, allows the use of both LAFWs and barrier isolators (called compounding aseptic isolators) in an ISO Class 7 buffer zone. However, if the manufacturer of a barrier isolator can prove that the isolator provides complete separation from the surrounding environment during dynamic operating conditions, the isolator does not have to be placed in an ISO Class 7 room. In total, the revisions “emphasize the personnel training and testing as well as the air quality and equipment and facilities necessary to meet the standard,” University of Oklahoma’s Allen says.

In his travels, Allen has noted a mix of cleanrooms with LAFWs and barrier isolation technology being used. “Generally, if a large volume of sterile preparations or IV admixtures is prepared, then workbenches with laminar airflow are easier to work with. If economics is an issue and the workload is low, then isolator systems are often selected,” he says.

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Figure 2. The MIC-EDU barrier isolator from Containment Technology Group is the result of four years’ collaboration with STERIS Corp. and is offered in both single- and dual-chamber models. It has a static airlock that allows for residence time for decontamination agents and for performing automatic decontamination of the compounding environment. Photo courtesy of CTG.

The isolator at The Compounding Shoppe is one of CTG’s MIC units, a line of equipment that incorporates a static airlock, which allows for residence time for decontamination agents. “Our documentation package for compliance to the 2008 revisions to USP <797> contains a study showing that the static airlock approach results in at least [a 30 percent reduction] of microorganisms compared to a dynamic airlock when using 3 percent non-sterile hydrogen peroxide,” says Hank Rahe, technical director with CTG. “We attribute the reduction of microorganisms to the airlock design and the airflow pattern within the isolator chamber.”

Rahe points to two primary factors that influence a pharmacy director’s decision to choose a cleanroom instead of isolator technology: the perception that compounding in a cleanroom is more efficient and that it requires less change or disruption to familiar staff routines. “The idea that an isolator represents change and tends to slow down compounding activities is the most common reason cited for not using isolator technology,” he says. “We addressed this issue early on and published a study that concluded that, when proper procedures are followed, an isolator is as productive as conventional engineering controls.”

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Figure 3. A pharmacy technician uses a Class 10 barrier isolator for sterile preparations. Photo courtesy of The Compounding Shoppe.

Another criticism is that, when using barrier isolators, people tend to relax their vigilance of protocol and other environmental controls because they feel the isolator will compensate for them. While isolators are less procedurally dependent than open cleanrooms, “good aseptic technique still needs to be practiced, and a properly trained staff understands the importance of maintaining the integrity of the environment in which sterile preparations are compounded,” Rahe says. “The isolator simply does not allow inadvertent touch contamination that can occur in open hoods.”

Monk-Tutor of the McWhorter School adds an important point: “Technique is always the key. The best equipment and cleanroom in the world will not make up for poor technique; they can only enhance correct technique,” she says.

On the pro-isolator side, reasons such as cost, flexibility, staff preference, safety, and increased sterility assurance typically are cited by pharmacy directors as reasons to use barrier isolators, Rahe says. Space utilization issues are common in hospital sterile compounding areas, and equipment design must accommodate these concerns. “Even though isolators are a less costly option, the flexibility an isolator offers is many times the deciding factor in selecting an isolator over a cleanroom,” Rahe says. “Cleanrooms represent a fixed asset and do not have the flexibility to relocate within a given facility or between facilities.” Furthermore, as opposed to being restrictive, isolators can actually be seen as enhancing the movement of pharmacists and technicians among different jobs, he says.

Other stipulations

Both isolators and LAFWs are referred to generically as primary engineering controls, or PECs, in USP <797>. Both must provide ISO Class 5 levels of cleanliness, but equipment specifications are just one part of the chapter’s scope. The net outcome of the chapter is that all CSPs be prepared in a manner that “maintains sterility and minimizes the introduction of particulate matter” and that final compounded products “maintain their labeled strength within monograph limits for USP articles, or within 10 percent if not specified, until their BUDs [beyond use dates].”1

The chapter addresses a number of different scenarios and types of products under the CSP umbrella. Hazardous drugs are one example. Using any PEC, hazardous drugs must be compounded in a negative-pressure buffer room, while non-hazardous drugs must be compounded in a positive-pressure buffer room. In addition, hazardous drugs must be stored separately from other inventory in a negative-pressure area.

“Hazardous drugs are a part of a pharmacist’s life: As long as a patient needs a hazardous drug that has been prescribed by a physician, pharmacists have the obligation to prepare it,” Allen says. “Safety precautions are now addressed in much more detail than they were years ago, so we now have good standards, practices, and new equipment to better handle hazardous drugs.”

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Figure 4. Cintas offers the same cleanroom garments and services to compounding pharmacies that it offers pharmaceutical manufacturing companies. These include sterile reusable coveralls, hoods, boots, and frocks constructed of its Integrity 1800 antimicrobial fabric. The company also supplies technician suits (cleanroom undergarments), sterile consumable products, and sterile disposable garments. Photo courtesy of Cintas Corp.

The concept of a segregated area is new in the revised chapter. Along with hazardous drugs, the chapter includes a section on compounding low-risk-level CSPs with 12-hour beyond-use dating in an ISO Class 5 PEC within a segregated area. The chapter similarly provides an Immediate Use Exemption from ISO Class 5, in which compounding with direct contact contamination in an environment lower than ISO Class 5 is permitted when no more than three sterile ingredients are prepared or combined for administration that begins within one hour and is completed within 12 hours of completing the CSP.

Realistically, Allen notes, “some pharmacies may be able to do low-risk but most probably end up doing low- and medium-risk work. High-risk is more limited but is necessary in many situations; it just depends upon the workload and market the pharmacy serves as to which risk level is utilized.”

Jan Eudy, corporate quality assurance manager with Cintas Corp. (Cincinnati, OH), affirms that building a cleanroom capable of handling the variety of CSPs encountered is a key challenge to achieving both USP <797> compliance and good quality systems in the pharmacy setting. “Examples include separate areas for chemotherapy or hormonal mixtures in a closed cleanroom system vs. nutritional mixtures in a laminar flow hood system,” she says. “These require proper segregation of product and processes.” The pharmacy must also be ready to “make the financial commitment to maintain the calibration of the equipment and the cleanroom cleanliness levels required,” she adds.

“Cross-contamination is constantly a concern due to the number of people working in the cleanroom and the variety of products and processes in the cleanroom,” Eudy says. “This issue is addressed by creating a comprehensive cleanroom cleaning/sanitizing program that addresses the contamination from personnel working in the cleanroom, the products and processes in the cleanroom, and any mechanized equipment used in the cleanroom.”

Back to school

Although USP <797> devotes extensive attention to the provision, maintenance, and evaluation of air quality, it is clear the avoidance of direct contact between gloves and surfaces in ISO Class 5 areas is paramount. The chapter states unequivocally, “Compounding personnel must be meticulously conscientious in precluding contact contamination of CSPs both within and outside ISO Class 5 areas.”1

This speaks directly to aseptic technique and the proper preparation of sterile drugs. The chapter specifies that compounding personnel must be adequately skilled, educated, instructed, and trained in the following activities: antiseptic hand cleansing and disinfecting of non-sterile compounding surfaces; selecting and appropriately donning protective garb; maintaining or achieving sterility of CSPs in ISO Class 5 PEC devices; protecting personnel and compounding environments from contamination by radioactive, cytotoxic, and chemotoxic drugs; identifying, weighing, and measuring ingredients; manipulating sterile products aseptically; sterilizing high-risk-level CSPs; and labeling and quality inspecting CSPs.

So where does one become educated and trained in these skills? University curricula, continuing education, and on-the-job training are options, but none of them, individually or in concert, are doing a particularly good job in filling the knowledge void created by USP <797>. Efforts are underway to improve the situation, of course, and most recently the American Pharmacists Association published its official education and training policies that reflect many of the issues raised by USP <797>.

“The level of training has been a problem for at least 20 years,” Allen says. “Pharmacy students today do not have the scientific and laboratory background that they used to obtain during their education. So many of them attend specialized training programs to obtain the education required to meet the <797> standards. This is one reason that the <797> committee is emphasizing personnel training and especially personnel testing in performing operations such as media fills and fingertip testing. This is a good and necessary step for ensuring proper procedures are followed.”

“Some states require CSP certification through a CE program that includes a test and a skills demonstration, but, in my experience, these programs only cover very basic skills and are not sufficient to provide any proficiency,” Monk-Tutor says. “Some involve as little as 10 or 15 minutes “under the hood.’ So, I do see a national skills certification program coming some time in the future, either through a national pharmacy organization or through a private company.”

For an assessment of the current state of affairs among U.S. schools of pharmacy, Monk-Tutor conducted a survey to assess the extent of didactic and laboratory instruction related to CSPs. Results published last November in the American Journal of Health-System Pharmacy showed that, overall, instruction varied widely and only about a sixth of respondents believed that their students were adequately trained in CSPs before graduation.

“Ideally, every school of pharmacy would have a state-of-the-art cleanroom and at least one faculty member who is experienced in infusion therapy and knowledgeable about USP <797> to teach students,” Monk-Tutor says. “Unfortunately, few schools have the financial resources and/or space available to build out a cleanroom, not to mention maintain it.” Another deficiency in her mind is that many pharmacy schools “do not seem to have an expert in infusion on faculty.”

Further findings from the study seem to put the onus on continuing and on-the-job education: Although only 13 percent of schools felt that their students had adequate CSP training before graduation, nearly 90 percent of them believed that students could only become fully competent in these skills over time in actual practice.

“In my experience and based on the literature I have seen, most continuing education programs on infusion are minimal and on-the-job learning varies drastically by site,” Monk-Tutor says. “Even though great resources, like those provided by ASHP [American Society of Health-System Pharmacists] and NHIA [National Home Infusion Association], are available to help train employees, not all organizations use these tools. One great way to get appropriate training in all schools of pharmacy is for schools to partner with local hospitals or infusion providers.”

Learning by doing

Equipment and service suppliers are also an important educational resource. Many of them also work with biopharmaceutical manufacturers and can apply the knowledge and experience from this industry to their clients in sterile compounding.

Cintas, for example, includes education and site assessments as part of its overall offering. A supplier of cleanroom garments and disposables, Cintas provides an education program based on IEST recommended practices and ISO 14644 guidelines on cleanroom protocol. This includes design of cleanroom linear product flow with line clearance; donning and doffing cleanroom garments; behavior/working in the cleanroom; cleaning of the cleanroom; environmental monitoring and testing of the cleanroom; and documentation and auditing of the cleanroom management program.

A sterile garment/gowning program should not be overlooked. “A cleanroom garment program that is USP <797>-compliant needs to replicate the cleanroom garment program currently in use by pharmaceutical manufacturers,” Eudy says. “This includes the recommended garment items, the validated laundry process, the validated sterilization process, and the assurance of consistent quality of product and services required by USP <797>.” Cintas’ Cleanroom Resources Division currently provides sterile consumable garments and supplies to a large compounding pharmaceutical company with 23 different locations throughout the United States, as well as to smaller compounding pharmacies.

CTG also offers a pharmacy assessment service that provides two types of information to the pharmacy. The first helps them understand the number and types of isolators that will best fit their given needs, and the second advises them how to configure the isolators economically to meet the facility’s volume of work. “Using the data the pharmacy provides, we can determine with our database the proper configuration of isolators and provide an economic analysis comparing the cost of a cleanroom to the isolators. This includes both capital and operating costs,” Rahe says.

To be sure, numerous companies design and build compliant cleanrooms for the various compounding risk levels; programs are available for training pharmacists and technicians and for providing continuing education; services exist to certify cleanrooms and laminar flow hoods; and analytical labs provide product QC including sterility and pyrogen testing.

“None of these are free, of course, but the essential component is a commitment by the pharmacist in charge to avail him/herself of these services and conscientiously carry out the QC program,” McPherson of Southern Illinois University says.

On this point, some observers find disconcerting the apparent reluctance to reach out to the pharmaceutical manufacturing community and translate some of its accumulated knowledge to pharmacy sterile compounding. “Some pharmacy consultants seem to have taken the position of “NIH’–“not invented here’–because they feel compounding is somehow different,” Rahe says. “While some aspects of compounding sterile products are different, a great deal of knowledge could be transferred from manufacturing experience-based individuals. One wonders what is the true motivation in not taking advantage of an outreach to other communities of knowledge.”


  1. United States Pharmacopeia, “USP General Chapter <797> Pharmaceutical Compounding–Sterile Preparations.” The revised USP <797> is available online at

Compounding Sterile Preparations Raises Informed-Consent Issues

BETHESDA, MD, 06 June 2003—Patients should be informed about the risks involved in using formulations that are compounded using nonsterile ingredients, which are at high risk for contamination with infectious microorganisms, said Robert E. Rapp, professor of pharmacy and surgery at the University of Kentucky at Lexington.

When a sterile product manufactured by a drug company is unavailable and a prescriber is requesting that a hospital’s pharmacy compound a sterile preparation from nonsterile ingredients or obtain a compounded sterile preparation from an outside pharmacy, a patient should be apprised that the formulation is not approved by FDA “and therefore the risk is greater” to the patient, said Rapp, who is chair of his university’s human investigations committee.

In addition to counseling a patient about the medication, he said, a health system’s pharmacy should give the patient an informed-consent form that outlines the risks and benefits of using the particular compounded sterile preparation.

A pharmacist must strictly follow guidelines issued by the United States Pharmacopeia when compounding sterile preparations, Rapp said, and ensure that the appropriate ingredients are used and that the formulation is the proper concentration, correctly labeled, and free from contaminants.

“There have been so many instances where pharmacists have [compounded sterile preparations] and then had [the formulations] recalled. If we can’t do it right, we shouldn’t be doing it,” he said.

Carmen A. Catizone, executive director for the National Association of Boards of Pharmacy, said that all state boards of pharmacy have regulations requiring pharmacists to notify prescribers when a commercial drug product is unavailable and a compounded sterile preparation must therefore be substituted.

Taking Full Responsibility

Joe O'Day, pharmacy services director for Faulkner Hospital in Boston, Massachusetts, said that when an ophthalmologist requested that the hospital's pharmacy obtain compounded hyaluronidase injection from an outside pharmacy, he and his assistant director, David Schraut, spent many hours researching where to obtain the compounded formulation and how to ensure that it would be safe and effective.

Hyaluronidase is used as an adjunctive agent to facilitate the dispersion and absorption of other drugs. It is used in ophthalmic surgery to enhance local anesthesia and to enhance the hypotonic effect of local anesthetics before cataract surgery.

Wyeth stopped manufacturing hyaluronidase injection in 2001, and there is no other FDA-approved source for the product.

As part of his research, O'Day consulted with other pharmacists, physicians, an FDA agent, and members of his hospital's pharmacy and therapeutics committee.

O'Day created a quality assurance checklist using the ASHP guidelines for outsourced compounding pharmacies and also developed a patient-consent form.

But, he said, he found himself in a quandary when two "widely-used and respected" pharmacies he was considering failed to assure him that the raw materials they used in compounding hyaluronidase had domestic origins.

Hyaluronidase is usually derived from bovine testicular tissue extracts. Use of foreign bovine tissue could potentially result in the development of bovine spongiform encephalopathy in drug recipients.

The certificate of origin used by one pharmacy O'Day had considered stated that the country of origin of its bovine tissue was the United States, but the certificate also stated that the animals obtained were from U.S. or foreign government facilities, he said.

The compounder also did not screen every batch of raw material for viral contamination, O'Day added, in conflict with the ASHP guidelines.

He and his hospital ultimately decided not to obtain hyaluronidase from a compounding pharmacy after an FDA agent strongly recommended against using a compounder to supply the formulation.

O'Day had also consulted with surgeons who advised him that alternative surgical techniques existed that did not require the use of hyaluronidase.

O'Day said he is concerned about the increasing number of drug products that are unavailable from manufacturers and the lack of control and oversight of compounding pharmacies.

When a manufactured product is unavailable and a prescriber wants to use a compounded sterile preparation from an outside pharmacy, health-system pharmacists must assume the additional role of scrutinizing the outsourced pharmacy, he added.

"Compounding is not my expertise," he said. "Requiring pharmacists to fulfill the role as FDA-inspector of products is inappropriate and can lead to patient harm."

But few states have regulations requiring pharmacists to inform a patient when a compounded sterile formulation is being substituted for a manufactured product, he said.

Catizone advised that “anytime the prescription is modified or changed and is different than a patient believes, contacting both the prescriber and the patient is good, sound advice.”

The Alaska Board of Pharmacy requires “both the patient and the prescribing practitioner [to] authorize the use of a compounded” preparation when it is being substituted for a manufactured product.

Missouri Board of Pharmacy Executive Director Kevin Kinkade said that his state has “left it up to the professional decision process about what information goes to the patient.”

But, he advised, when a product manufactured by a drug company is unavailable, “to avoid confusion, a pharmacist should explain to the patient that a compounded preparation has been substituted.”

Gay Dodson, executive director of the Texas State Board of Pharmacy, said her state adopted a regulation last year requiring pharmacies that outsource prescription dispensing, including compounded formulations, to notify patients regardless if a substitution is made. The provision, however, applies only to outpatient and community pharmacy settings, not to patients in hospitals or nursing homes.

Pharmacist and attorney Jesse C. Vivian, a professor of pharmacy practice for Wayne State University College of Pharmacy in Detroit, Michigan, said that, from an ethical standpoint, he would inform a patient when a compounded sterile formulation has been prescribed.

But, he added, patient consent forms should be considered on a case-by-case basis.

Pharmacy, Vivian noted, has ranked high among trusted professions. Compounding is a historical function of the profession and, with the increasing number of drug shortages, pharmacists are more frequently compounding preparations.

But, he added, pharmacy schools and technician training programs do not provide practitioners with adequate compounding skills.

Jane J. McCaffrey, risk manager for Oconee Memorial Hospital in Seneca, South Carolina, and president of the American Society for Healthcare Risk Management, said that when a high-risk procedure is involved, including the use of a compounded sterile preparation, most organizations make their own determinations about what information to provide to patients.

But, she counseled, when the use of a compounded sterile formulation is inherently risky, a patient should be involved in making decisions about his or her care.

Health systems should weigh the risks of using compounded preparations, McCaffrey said.

If a risk is significant or unknown, or the use of the compounded formulation is considered experimental with no supporting literature about patient outcomes, McCaffrey would advise against using the preparation.

If a health system does not require patients sign a consent form before receipt of a high-risk compounded sterile preparation, she said, and something goes wrong, the organization should be prepared to prove that it adequately explained the risks to patients.

A pharmacist should verify that a patient has been informed by the prescriber about the use of a compounded sterile preparation before dispensing the formulation, McCaffrey said.

While pharmacists have the best knowledge base about drugs and should counsel patients about their medications, she said, prescribers should be responsible for discussing a patient’s care, including explaining medications, directly with a patient and should not defer that responsibility to a pharmacist.

What is a "Compounded Sterile Preparation" According to USP Chapter 797?

USP Chapter 797 deals with policies and practices for compounding sterile preparations safely and without contamination. A compounded sterile preparation (CSP) is a dosage unit that:

  • Is prepared according to the manufacturer's labeled instructions
  • Contains non-sterile ingredients or uses non-sterile components or devices that need to be sterilized before use
  • Is a biologic, diagnostic, drug, nutrient, or pharmaceutical that matches either of these characteristics

Examples include baths and soaks for live organs and tissues, implants, inhalations, injections, powder for injection, irrigations, metered sprays, and ophthalmic and otic preparations.

USP 797 includes specific information about preparing, storing, and administering CSPs. Sections include -

  • Microbial risk levels
  • Expiration dating
  • Packaging, chemical stability, and product integrity
  • Validations and media fills
  • Compounding accuracy

Microbial Risk Levels

USP 797 assigns each CSP to one of three potential contamination risk levels: low, medium, or high. The risk level a CSP is assigned to depends on its compounding environment; its potential for microbial, chemical, and physical contamination; and the nature of production of the CSP (for example, using automated filling equipment or reservoirs of injection and infusion devices).

Below are examples of the three risk levels for CSPs:

Low-Risk Level

Low-risk level compounding occurs in an ISO Class 5 environment and involves only a few basic, closed-system steps. Specific examples include the following:

  • Reconstituting single-dose vials of antibiotics
  • Preparing hydration solutions
  • Compounding CSPs from sterile commercial drugs using commercial sterile devices

Medium-Risk Level

Medium-risk level compounding involves complex procedures that may occur over a prolonged period of time. It also includes using pooled sterile commercial products for multiple patients, or for one patient multiple times.

Specific examples include the following:

  • Chemotherapy or pain management administered by an infusion device
  • Pooled admixtures
  • Batched antibiotics
  • Parenteral nutrition solutions using automated compounders
  • Batch-compounded preparations that do not contain bacteriostatic components

High-Risk Level

High-risk level compounding occurs when

  • CSPs are prepared from non-sterile ingredients
  • CSPs are prepared from sterile ingredients, but the environment is not ISO Class 5
  • More than six hours passes between compounding and sterilization
  • The purity of compounds is not verified by documentation

Specific examples include the following:

  • Preparing CSPs from bulk, non-sterile components, such as morphine (always high-risk)
  • Using final containers that are non-sterile and must be terminally sterilized
Compounded Sterile Preparation

Expiration Dating

Expiration dating refers to how long a CSP can be stored and at what temperature.

Packaging, Chemical Stability, and Product Integrity

This section of USP 797 requires that the packaging selected for CSPs is appropriate to preserve its sterility and strength until the beyond-use date.

Validations and Media Fills

USP 797 outlines different media-fill procedures that compounding professionals can perform at their facilities, depending on the risk category of the CSP.

Compounding Accuracy

USP 797 also sets requirements for compounding accuracies. Automated-filling machines must be carefully calibrated and fill volumes verified.


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What is known about the Acai berry fruit health benefits, backed by scientific research into the fruits properties, is quite substantial. Acai is a rich source of anthocyanins and other phenolics and phyto-nutrients. Acai berries are amongst the most nutritious foods of the Amazon, rich in B vitamins, minerals, fiber, protein and omega-3 fatty acids. Acai also contains oleic acid (omega-9), a beneficial fatty acid (often mistakenly referred to as essential).

Minerals found in Acai Berry: Potassium is the mineral most abundant in the Acai. Acai is also rich in copper, and unusually high in manganese. Only a small portion supplies far more than the body needs of this ultra-trace mineral.

Acai Phytonutrients: Anthocyanins are compounds that have potent antioxidant activity, allowing for the neutralization of potentially harmful free radicals. The famous research regarding the "French Paradox" attributes anthocyanins as being the antioxidant that protects the French from heart disease. The French are known to consume large amounts of coffee, nicotine, sugar, white flour, cheese and saturated fats, yet they have a very low rate of heart disease compared to neighboring countries like the UK and Denmark. The red wine grape, due to its anthocyanins is what is believed to be responsible for the very low incidence of heart disease. While red wine has good quantities of anthocyanins, the Acai berry has been shown to contain many times the anthocyanins levels of red wine.

By neutralizing these free radicals, anthocyanins from the Acai berry may actually serve to maintain the healthy function of numerous systems and organs. Some of the anthocyanins that have been found in Acai include cyanidin-3-glucoside and cyanidin-3-glucoside-coumarate. Other phenolics include catechin and epi-catechin (the same compounds in green tea), quercetin derivatives and other flavonoids. It is likely that the synergistic effects of these compounds, as present in Acai fruit are responsible for its potent antioxidant activities.

ORAC Scale: The Oxygen Radical Absorption Capacity (ORAC) assay measures the total antioxidant activity of a biological sample. It’s a test developed for the USDA by scientists at Tufts University to measure the antioxidant speed and power of foods and supplements. The ORAC scale is used in human, agricultural, food and pharmaceutical products, as well as food ingredients and is quickly becoming the accepted standard for comparing antioxidant potential in foods and supplements.

Acai Antioxidant Benefits: For the average Western person to cope with all the reactive oxygen and free radicals they will encounter on a daily basis, foods and beverages totalling an ORAC value of at least 2000 units per day are needed. It’s been estimated that 80-90 percent of the world’s population fails to consume even half of this level. Acai is reputed to be extremely high on the ORAC scale and provides levels multiple times that of many anthocyanin-rich fruits and vegetables, such as cherries, cranberries and mulberries.

Aging Population: As the population ages, 80% of older people in Western countries will develop at least one chronic metabolic disease. If the USDA says that high-ORAC foods may slow aging and prevent metabolic disease from occurring, isn't it about time you increased the quantity of antioxidants in your diet to prevent this process from occurring in the first place?

Weight loss: Very helpful in losing weight. just add it in your diet ( capsules are best).

Saturday, August 8, 2009

Selecting The Right Agent For Sterilization

Choosing the right sterilizing/decontaminating agent for your cleanroom can be both an easy task and a daunting choice.

The optimal agent should be classified and registered as an antimicrobial pesticide with the United States Environment Protection Agency (EPA). Antimicrobial pesticides are substances or mixtures of substances used to destroy or suppress the growth of harmful microorganisms, such as bacteria, viruses, or fungi, on a variety of objects and surfaces. Antimicrobial pesticides have two major uses:

  • To disinfect, sanitize, reduce, or mitigate growth or development of microbiological organisms.
  • To protect objects (floors and walls, for example), industrial processes or systems, surfaces, water, or other chemical substances from contamination, fouling, or deterioration caused by bacteria, viruses, fungi, protozoa, algae, or slime.

The Federal Government carefully regulates pesticides to ensure that they do not pose unreasonable risks to either human health or the environment, and as part of that effort, requires extensive test data from antimicrobial pesticide producers that demonstrate as such. EPA scientists and analysts carefully review these data to determine whether to register (license) a pesticide product or a use and whether specific restrictions are necessary.

When performing any disinfection, decontamination, or sterilization, the user must remember what is being accomplished; the maximum kill of the target organisms with a minimal amount of hazard to the user. All appropriate safety precautions should always be taken as all of these methods pose some risk to humans. In terms of safety, liquid-based systems are probably the safest since most of the agent is contained in solution; however, there is some off-gassing that occurs with different liquid agents. The vapor and gassing systems are all equally harmful to people. As such, the rooms must never be entered during the decontamination process because the concentration of sterilant in the room is high enough to be harmful to humans.

Is This a Convenient Time to Clean?

Asking if it’s a convenient time to clean is equivalent to asking: “Is this a convenient time to extract your impacted molars”? The simple answer is “No.” There’s never a convenient time to clean (or remove impacted molars). Cleaning does not have any associated technical glamour or appeal — it tends to be considered a necessary evil and is therefore always inconvenient.

No one comes to work in the morning excited about the prospect of cleaning. To make matters worse, often cleanroom surfaces don’t look any different after cleaning. Cleaning is also viewed as a disruption to the orderly flow of manufacturing; ostensibly, if you are cleaning, you cannot be making product.

On the one hand, cleaning is a recognized requirement for minimizing contamination in cleanrooms. But in practice, these activities are often postponed, compromised, or ignored. When this occurs, air-borne or contact-transferred contaminants will accumulate on critical surfaces and unless they are removed by regular cleaning activities — for example by wiping — these contaminants can affect processes, products and yield. It may seem incongruous that a low-technology activity such as the wiping of surfaces can be effective in controlling contamination in modern, totally-automated, multi-billion dollar semiconductor manufacturing facilities, but there is no substitute for the surface energy that wiping provides to remove contaminants and the subsequent containment of those contaminants within the wiper fabric.

A convenient time to clean occurs when operators are trained and when cleaning products (i.e., wipers) are conveniently available. Convenience, surprisingly, translates to protocol adherence, and consequently, cleaner cleanrooms. Regrettably, there’s still no convenient time to extract impacted

Effective Swabbing Techniques For Cleaning Validation

How To Succeed In The Search For Nothing:

Assuming the surface is free of visible residue (i.e., that the cleaning stage is done), the challenge is now to sample that surface in a reproducible manner so that any (invisible) residues, present in extremely small amounts, are collected and delivered to the instrument for measurement.

The best type of swab for sampling is one with a head made of laundered polyester knit fabric, since that material provides the lowest levels of releasable particles, the highest recovery, and the lowest background when total organic carbon (TOC) measurements are employed as the analytical technique. To sample the surface, the swab is moistened then drawn across the surface in a thorough and reproducible manner to collect any residue into the interstices of the polyester knit fabric. The swab is then deposited into a suitable collection vial, then the residues extracted from the swab head for subsequent anaysis.

There might be a temptation to simply saturate the swab head with high-quality (e.g., TOC-grade) water to do the residue collection. This will cause problems, since the excess liquid on the swab head will simply spread the residue over the surface to be sampled and will not allow the residue to be picked up reproducibly into the swab fabric. For best results, the swab should be damp, but not saturated. This is best accomplished by immersing the head into a container of high-quality water, and pressing both sides of the swab head against the side of the container a few times to expel any air trapped in the fabric and allow the water to fully penetrate the fabric. Then the swab head is raised out of the water and the flat sides of the swab are drawn across the rim of the container to expel excess water and leave the swab head moist. The degree of moistness of the swab head (otherwise known as the percent wetting level) need not be identical from run to run, since residues will be picked up over a fairly wide range of swab head moistness.

The manner in which the swab is used to sample the surface (i.e., the swabbing pattern) is critical to ensure accurate and reproducible collection of residues. For easily accessible surfaces, a template with a 5 cm opening can be used to sample the same surface area each time. As with wiping, linear overlapping strokes over the surface to be sampled will ensure that the residue is collected into the moist swab head. The first side of the first swab is swiped horizontally ten times over the template opening, then the swab is flipped over and the second side is swiped vertically ten times over the same surface. This swab is deposited into the collection vial. The first side of the second swab is swiped diagonally upwards ten times, then flipped over and the second side swiped diagonally downward ten times. The second swab is deposited into the same collection vial. In this manner, the surface has been swabbed a total of 40 times, and there is a reasonable expectation that any residue on the surface has been transferred into the two swab heads. It is not required to use two swabs; often one will do.