ARL’s out-of-specification investigations use a hybrid approach to review data, formulations, and tests. Our data reviewers consult with ARL’s scientific directors and clients to ensure we provide a 360-view investigation and evaluate all aspects of the laboratory, data, and client and analyst trends. Typical investigations are concluded within one week or within 4 business days after the due date.
United States Pharmacopeia monographs establish standards for identity, strength, quality, and purity of medicines. Monographs list tests and acceptance criteria (usually expressed in percentage ranges or limits). Drug substances and products should meet the acceptance criteria to be considered acceptable for its intended use. An Out of Specification (OOS) occurs when a test fails to meet acceptance criteria. An OOS Investigation follows an OOS test result and is performed to determine if there is a root cause. In this article we will look specifically at potential causes of potency OOS results of finished drug products. Understanding the factors that contributed to the potency failure allows the pharmacist and laboratory to define a strategic approach in eliminating future failures. The more specific the findings, the easier it is to properly address the cause.
The United States Pharmacopeial Convention, Inc. recommends within the standards of the United States Pharmacopeia that compounding pharmacies have staff dedicated to quality assurance and quality control to ensure patients are receiving safe medications. The quality-control program must include testing. While compounding pharmacies have grown familiar with potency, sterility, and endotoxin testing, there are many more tests recommended within the United States Pharmacopeia that are critical for evaluating the quality of compounded preparations. This article discusses when a few of these tests should be utilized, how to assign acceptance criteria, and how test results are obtained.
USP <60>, Microbiological Examination of Nonsterile Products – Tests for Burkholderia cepacia Complex, describes a test procedure that evaluates the microbiological quality, specifically the presence of species of the genus Burkholderia, in non-sterile substances and preparations. This is important, because Burkholderia is a potentially dangerous pathogen, especially for drugs or raw materials that are intended for inhalation use, and aqueous preparations for oral, oromucosal, cutaneous, or nasal administration.
There are several clinical reasons why it is important to screen for this genus of microorganisms. First, they are Gram-negative, indicating their presence will produce endotoxins, potentially triggering a pyrogenic effect in a patient. Burkholderia is an opportunistic pathogen, commonly causing pneumonia in immunocompromised persons or those with existing lung diseases. Lung infection from Burkholderia is dangerous, and is characterized by a steep decline in function, potentially resulting death. According to Lyczak (2002), death rates can be nearly 5x higher in Cystic Fibrosis (CF) patients infected with Burkholderia vs non-infected CF patients. This, combined with its ability to spread person to person via body fluids, generally results in strict isolation procedures if detected in the hospital setting. Burkholderia are naturally resistant to many antibiotics, including aminoglycosides and polymyxin B. Treatment generally requires a combination of several antibiotics. Combinations of ceftazidime, doxycycline, chloramphenicol, and others have been used as successful treatment options.
Just as crucial as the sterile production of drug products is ensuring those same products are free of dangerous pyrogens - contaminants that induce febrile reactions in patients if introduced at high levels.
Relative to patient safety, the most concerning and common pyrogen is bacterial endotoxins. Pyrogens can be removed or destroyed by depyrogenation. A common method for depyrogenation is dry heat. Largely reproducible and easily controlled, dry heat depyrogenation is dependent on temperature and time to eliminate bacterial endotoxins. The depyrogenation process can be qualified and monitored with Endotoxin Challenge Vials (ECVs).
Ophthalmic medications must meet particulate matter test requirements. Particulate matter may come from foreign or product-related substances. Clinical exposure to unwanted particulate matter can cause a biological response in patients including blocking capillaries and arteries, introducing microorganisms and causing an infection, or causing an allergic reaction.
A cleaning validation demonstrates a pharmacy, hospital, or outsourcing facility's cleaning procedure is effective and consistent in cleaning equipment and compounding surface areas. The Food and Drug Administration (FDA) expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. According to the FDA, 21 CFR Part 211, "Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements." A cleaning validation is how one proves their cleaning SOPs are sufficient.
According to Center for Disease Control and Prevention (CDC), over 8 million US healthcare workers are exposed to hazardous drugs (HDs) every year. Drugs classified as hazardous include cancer therapy, antiviral drugs, hormones, and bioengineered drugs.
More than 12 billion doses of HDs are handled by US providers each year. Anyone handling HDs is at risk of exposure to acute and long-term effects including hair loss, cardiac toxicity, kidney damage, hearing loss, nausea, rashes, cancer, and infertility.
According to the FDA, ensuring data integrity is an important component of industry's responsibility to ensure the safety, efficacy, and quality of drugs. ARL Bio Pharma has GMP software that controls our laboratory's instruments and generated data. This software complies with 21CFR Part 11 as it relates to electronic records. All data is locked down and backed up so ARL can retrieve information in its native format with tracked changes and modifications. Our validated software meets FDA's expectation for GMP Compliance to provide our clients with data integrity critical to the GMP data lifecycles.
To learn more about Data Integrity and Compliance with Drug cGMP, click here.
Cannabidiol (CBD) is a naturally occurring compound within the cannabis plant. It is often sold as an oil, consisting of CBD and a carrier oil such as grape seed or hemp seed oil. The dosage of CBD within these manufactured products can vary greatly in potency depending on dosage forms including oral administration (oil) or topical use (cream). CBD, as sourced from hemp plants, should typically contains less than 0.3% Delta-9-Tetrahydrocannabinol (THC) by weight. Conversely, CBD as sourced from Marijuana plants may contain up to 40% of THC by weight. To bolster consumer confidence in these products, it is critical for accurate quantification of CBD in formulated products, with corresponding demonstration of low THC content per state requirements.
ARL Bio Pharma employs High Performance Liquid Chromatography (HPLC) as our standard testing methodology for CBD quantification. We routinely test CBD oils and creams for CBD potency. We also offer a THC limit assay to demonstrate that THC is not present in the product formulation down to a concentration of 0.3%.
Contact ARL at info@arlok.com or 800-393-1595 to discuss your CBD testing requirements.