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USP Monographs

The United States Pharmacopeia (USP) is a non–governmental, official public standards–setting authority for prescription and over–the–counter medicines and other healthcare products manufactured or sold in the United States. USP also sets widely recognized standards for food ingredients and dietary supplements. USP sets standards for the quality, purity, strength, and consistency of these products–critical to the public health. USP’s standards are recognized and used in more than 130 countries around the globe. These standards have helped to ensure public health throughout the world for close to 200 years. USP Monographs are standards that specify the quality attributes of thousands of ingredients, raw materials excipients and finished products sold in the United States. These standards are recognized as official by the United States Food and Drug Administration. An example of a USP Monograph is Aspirin.

The nine quality attributes that must be certified by qualified laboratories such as Gibraltar Laboratories are listed below

USP Aspirin

C9H8O4 180.16

  1. Identification—
  2. Loss on drying 731
  3. Readily carbonizable substances 271
  4. Residue on ignition 281:
  5. Chloride 221—
  6. Sulfate
  7. Heavy metals
  8. Limit of free salicylic acid
  9. Assay
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Microbial Limits Testing

At Gibraltar Laboratories one of the most frequent questions we are asked about is what is the proper way to examine non-sterile products?  It is easy to test a sterile product because it is understood that the absence of pathogenic bacteria, yeasts and molds is expected. However, for non-sterile products it is understood that microorganisms are likely to be present. For ingredients or products specifically found in the USP/NF chapter 61 and 62 describe what needs to be done to perform and validate the test. Chapter 61 , Microbial Examination of Nonsterile Products: Microbial Enumerations tests describes how to determine how many organisms are present or the sample’s Bioburden. Chapter 62,  Microbial Examination of Nonsterile Products: Tests For Specified Organisms describes how to determine by microbial identification if specified organisms are present in the sample. Sometimes sponsors choose a similar test for the same purpose. If so, it cannot be called by the official USP name. In this case the test name may be Microbial Limits or Microbial Content. All of these tests share the common purpose of determining in a sample the number of organisms [colony forming units, CFU] present per gram. In many cases, regardless of the cfu/gram the sponsor applies a quality attribute to not accept certain organisms. The kinds of organisms that are not allowed are recognized to be pathogenic especially to the young, infirmed or otherwise immunocompromised patient. For example E.coli, Pseudomonas aeruginosa, Burkholderia , Staph aureus and Bacillus cereus are widely thought of as specified organisms to not allow to be present in the final product. However, there are many other organisms that are similar that may also pose a serious safety risk. For this reason, the sponsor must evaluate the kinds of organisms that are discovered during the enumeration testing. This is done by skilled microbiologists using sophisticated technologies such as the  Vitek biochemical identification and sometimes also by Genetic analysis. Gibraltar Laboratories is certified to help you with these important tests and performs them routinely with a  very fast turnaround time. In fact, our laboratory was the 2010-2011 winner of the ACIL Turn Around Time Award.

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Cytotoxicity Tests

Cytotoxicity tests are performed at Gibraltar Laboratories for many different applications. The classic cytotoxicity tests
found in the USP is “<87>, Biological Reactivity, in vitro”. It is designed to determine the biological reactivity of mammalian fibroblast cells [L-929 (ATCC cell line CCL 1, NCTC clone 929) following contact with the elastomeric plastics and other polymeric materials with direct or indirect patient contact or of specific extracts prepared from the materials under test. Three cytotoxicity tests are described (i.e., the Agar Diffusion Test, the Direct Contact Test, and the Elution Test). The decision as to which type of test or the number of tests to be performed to assess the potential biological response of a specific sample or extract depends upon the material, the final product, and its intended use. Other factors that may also affect the suitability of sample for a specific use are the polymeric composition; processing and cleaning procedures; contacting media; inks; adhesives; absorption, adsorption, and permeability of preservatives; and conditions of storage. Evaluation of such factors should be made by appropriate additional specific tests before determining that a product made from a specific material is suitable for its intended use. Any leachable cytotoxic materials are extracted from the plastic using Sodium Chloride Injection containing 0.9% of NaCl or serum-free mammalian cell culture media or serum-supplemented mammalian cell culture media.

In the USP test grading of cytotoxicity is semi-quantitative. Changes in the cell morphology or the presence of cell damage are scored on a scale of 0-4 with 0 meaning no cell lysis and 4 meaning Severe%, damage or destruction.

In comparison, “ISO 10993-5 Biological Evaluation of Medical Devices-Part 5: Tests for in vitro cytotoxicity” provides further guidance and options including more targeted quantitative measurements using analytical instruments to quantitatively measure cellular activity. Thus, ISO groups measurements of cytotoxicity determination into four groups.

1) assessments of cell damage by morphological means [like USP];

2) measurements of cell damage;

3) measurements of cell growth;

4) measurements of specific aspects of cellular metabolism.

Using these sophisticated tests2-4 above Gibraltar Laboratories helps researchers to investigate potential anti-cancer and anti-viral drugs.

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ICH Stability Testing – Gibraltar Laboratories

Gibraltar Laboratories is a respected testing laboratory providing stability testing. Our stability tests are ICH compliant, adhering to the guidelines and best practices recommended by the International Conference on Harmonization (ICH).

What is ICH stability testing? By performing the ICH stability test, a drug, device, biotech manufacturer obtains rapid assurance that the given product will be safe and effective for the entire duration of the product’s stated shelf life. This is a critical regulatory requirement. Gibraltar Laboratories conducts ICH stability testing at room temperature to effectively reproduce real-life storage conditions. To simulate longer spans of storage, we are also capable of conducting “accelerated” stability testing which is done at temperatures up to 55 °C.

Gibraltar Laboratories uses advanced digital systems to monitor our test chambers 24 hours a day, helping ensure that temperature and humidity conditions are under control. We store samples under exactly defined conditions that are continuously documented. Three lots are placed in the chamber and the stability indicating tests chosen by the sponsor are performed. For example, potency, sterility, package integrity are assessed. Using 40C as the acceleration temperature [and the Arrhenius equation] one can forecast that in only three months the expected outcome of one year’s storage at 20C. As the temperature is further increased, for example to 55C for package integrity assessment , only one month is required to forecast the expected outcome of the test attribute after one year’s storage at 20C.

For ICH stability testing and our full list of test services, click here.

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Chemistry Testing

Gibraltar Laboratories provides chemistry testing and wet chemistry services for businesses, research institutions and government agencies both domestically and abroad. We specialize in analytical chemistry, microbiology, virology, validations/calibrations, biopharmaceuticals, chemistry and environmental monitoring services. Our focus lies in preclinical and other early stage product and process development to ensure safety, regulatory compliance and speed-to-market.

With chemistry testing services custom-tailored to our client’s unique needs, Gibraltar Laboratories ensures accurate and reproducible results for clients, whether they are in the United States, North America, even Europe or Asia. Our entire offering of chemistry testing services fully satisfies all applicable USP, EP, ISO, BP, AOAC, and AAMI/JP requirements.

Using the latest in chemistry testing equipment, trust Gibraltar to intelligently qualify raw material vendors critical for biotech products and drug manufacturing. Raw data is reviewed by the Chemistry department study director and analyst, subsequently reviewed independently by the Chemistry Quality Assurance Department following melting point, heavy metal, Karl Fisher, TOC, Conductivity and residual solvent testing as per CGMP. Gibraltar provides expert cleaning validation support.

For a full listing of our laboratory testing services, please visit our services page here.

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Total Organic Carbon

Total Organic Carbon (TOC) is a highly powerful analytical chemistry method that is valuable for many types of determinations. Two of the most common uses of Total Organic Carbon testing are for Purified Water testing and Cleaning Validations.  Gibraltar Laboratories excels in these areas because we use state of the art equipment manufactured by Sievers and our scientists are extensively trained and proficient.

Purified Water is water obtained by a suitable process. It is prepared from water complying with the U. S. Environmental Protection Agency National Primary Drinking Water Regulations or with the drinking water regulations of the European Union or of Japan, or with the World Health Organization’s Guidelines for Drinking Water Quality. It contains no added substance. The purity is judged by the absence of trace amounts of organic matter which is measured by the Total Organic Carbon test.

Total Organic Carbon is an indirect measure of organic molecules present in pharmaceutical waters measured as carbon. Organic molecules are introduced into the water from the source water, from purification and distribution system materials, and from biofilm growing in the system. Total Organic Carbon  can also be used as a process control attribute to monitor the performance of unit operations comprising the purification and distribution system. A Total Organic Carbon measurement is not a replacement test for endotoxin or microbiological control. While there can be a qualitative relationship between a food source (TOC) and microbiological activity, there is no direct numerical correlation. In addition to TOC, Purified Water must also meet the requirements of being relatively non-conductive as well as not harboring microbial coliforms such as E. coli. Customers typically rely upon Gibraltar Laboratories to quickly determine if the water they rely upon meets the requirements of purity such as low level of TOC, low conductivity and the absence of coliforms. Because Total Organic Carbon testing is so sensitive special care is needed to sample water. For example, the glassware used to collect the water must be specifically certified for use in TOC analysis or the determination will not be accurate. In addition, glassware used to collect samples must not be exposed to alcohol. Alcohol, such as ethanol, is a very useful step to control microorganisms but its use is detected and produces high TOC determinations leading to unnecessary investigations and/or OOS documentation.

Cleaning validation is performed to demonstrate that a new manufacturing campaign will not be contaminated by ingredients or cleaning agents previously used on common equipment. Since Total Organic Carbon is a non-specific measurement of carbon, it has wide spread application for companies that must comply with regulatory requirements. Typically, the manufacturer must assure that the active ingredients, excipients and cleaning agents used in a previous process are effectively removed so as to not be present as contaminants in a subsequent process. Since TOC can detect levels in the part per billion range it is possible to demonstrate that the equipment is not just visually clean but that it is clean scrupulously clean.

Gibraltar Laboratories is available to help and assist you to write validation protocols and reports to meet your needs. Please contact us for more information on Total Organic Carbon and other testing laboratory services.

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Exciting Cancer and Molecular Biology Research at Gibraltar Laboratories

Research and Analysis

Gibraltar is busily involved with confidential cancer research, stem cell research and antiviral research.. An example of this category of research recently appeared in C&EN. As funding levels for cancer combating drugs reach an all-time high, scientists and researchers are turning to new, innovative techniques in their quest for medical breakthroughs. Gibraltar is at the cutting edge of offering the kinds of molecular services needed to advance breakthroughs in the treatment of difficult medical conditions.  For example, PI3Ks, formally known as phosphatidylinositol-3 kinases, are enzymes that are inherent in a vast amount of functions involved in facilitating a cell’s ability to perform properly. PI3Ks have become palpable targets for researchers developing cancer drugs.

The many intriguing aspects surrounding the correlation between tumors and PI3Ks have prompted numerous drug companies to ramp up research into the inhibition process. Biotech firms have even been established for the sole purpose of developing drugs which target the pathways that control normal cell growth and their subsequent role in sparking the development of cancer should they be defective. And while the promise for a major advance in battling cancer is possible, the process by which PI3Ks are properly utilized remains just as complicated as many had anticipated. Still companies remain optimistic that the compounds which block this signaling pathway will eventually be vital to cancer treatment. As such, the race to run clinical trials testing the effects of combining PI3K inhibitors with other drugs has greatly intensified.

Gibraltar Laboratories offers in vivo chemotherapy research,  advanced molecular techniques involving western blot analysis and stem cells to support efforts to test hypotheses. Ultimately, the researchers goal is a solution that knocks down cancer cells without being too toxic to normal cells. Fortunately researchers now have the benefit of understanding a molecular mechanisms and thus have gained insight into both the best drug combinations and which patients will most sufficiently respond. Gibraltar is proud to be part of this exciting race to cure and improve patient outcomes.

 

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Tracking Your Information-Gibraltar Report Portal

Dear Gibraltar Friend,

As you have noticed we have improved our appearance recently. We have updated our logo to emphasize our widely known  company name. At  the same time we have updated our web page which makes it easier than ever before to do business with us. For example, now you can login to see a historical record of all of the reports that have been completed over the last six months. This makes it easier for you to verify that reports from us have been delivered and therefore the corresponding invoice should be approved for payment. In addition, if a report was misplaced you can conveniently login to review and download it. If you have not set up your account please contact us at 973.227.6882 or write me at DanielPrince@gibraltarlabsinc.com.

Sincerely,

Daniel Prince, Ph.D.

President