AGILENT TECHNOLOGIES PRACTICAL SOLUTIONS NEWSLETTER

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1 AGILENT TECHNOLOGIES PRACTICAL SOLUTIONS NEWSLETTER Volume 15 Issue 1 In This Issue: Meeting Filtration Requirements with the Agilent 850-DS Proposed Changes to Testing Gelatin Capsule Shells with Cross-linking Dissolution Source Book Triple Play Tips and Tricks to Improve Your Dissolution Testing Meeting Filtration Requirements with the Agilent 850-DS Dissolution testing involves two stages: sample preparation in the dissolution apparatus, and sample analysis. Filtration is an essential step to ensure the sample is representative for a given time point; the time at which a sample is withdrawn from the dissolution vessel and is immediately filtered marks when the dissolution process stops. Once cleared of solid particles and excipient material, the sample is now ready for analysis the second test stage. The analysis of filtered samples is generally performed by UV-Vis spectrophotometry or HPLC; the analytical method may impact the type of filtration required to ensure sample integrity. For instance, sub-micron filtration may be needed to reduce potential blockage of HPLC column inlets caused by particulates and excipient matter from sample solutions, to extend column life. Whether a dissolution method is performed manually or automatically, filters must be challenged for efficiency, adsorption, and leachability. If excessive absorption of the active drug occurs, excipient interference is high, or filters become clogged, alternative filters may be required. Filtration Capability of the 850-DS The 850-DS Dissolution Sampling Station can be used with cannula tip filters and/or an optional automated filter changer that can greatly improve the processing of dissolution samples through the use of innovatively designed filter plates. Changing the filters between time points lessens the risk of the filter becoming clogged and helps eliminate erroneous results from particles trapped on the filter from the previous time point. The system utilizes filter plates that are consistent with filtration membranes and housing materials currently used for dissolution sampling, made by GE Whatman specifically for use with the Agilent 850-DS. The only differences between traditional luer-type syringe filters and the filter plates are the absence of the luer fittings and the inclusion of eight disks on a flat cartridge. The compact arrangement of the filter disks on the filter plate continued on p. 2

2 Meeting Filtration Requirements with the Agilent 850-DS... continued also makes it much easier for automated equipment to process and filter samples, as compared to traditional automationready filters. For most purposes, the filter plate would require minimum validation for methods requiring the identical filter membrane when a method has been validated for a specific filter membrane or equivalent. Otherwise, filter revalidation may be performed with the abbreviated filter validation protocol for efficiency and adsorption. To ensure the integrity of the sample filtrate, it is necessary to demonstrate that the performance of the GE Whatman filter plate is equivalent to that of the filter currently in use, and that the required volume to saturate the filter with active drug is the same. For optimal performance, Agilent Full Flow pre-filters should be in place on the sampling cannulas to prevent larger particles from entering the sampling system. If particles of undissolved active Agilent Full Flow Filters drug are allowed to enter the sampling lines and flow path, dissolution results may be inadvertently increased due to further dissolution of active drug particles through shear forces and turbulence within the sampling system. Use of a Full Flow pre-filter can also prevent clogging of the finer pore size filters, and may even allow for multiple uses of the same filter plate. Another way that the sample integrity can be maintained is by verifying adsorbance of the active drug on the filter, and determining the amount of sample that must be passed through filters to keep active drug from binding to the filter materials. Agilent has provided a thorough filter validation template for the 850-DS that may be helpful in the development of new dissolution methods, in method transfer, and in exploring the use of alternative filters. Download the Agilent Filter Validation Protocol at chem/ en Learn More If you have questions regarding this protocol, feel free to contact the Dissolution Hotline at dissolution. hotline@agilent.com. Agilent 850-DS with Optional Filter Changer and Filter Plates Proposed Changes to Testing Gelatin Capsule Shells with Cross-linking 2 Problems associated with cross-linking in gelatin capsules have been prevalent enough that a USP Workshop on Dissolution Testing of Capsules was conducted to discuss improvements to USP Chapters <711> and <2040> in order to find optimum ways to address the issue. Cross-linking of capsule shells has been one of the most challenging aspects of dissolution testing in recent years. Cross-linking is the formation of new bonds between gelatin and itself, aldehydes, free radicals, etc., especially in the presence of light, heat, and humidity. When this occurs, the capsule shell becomes resistant to opening and can slow or prevent the active drug from dissolving. Most commonly, this change is visible, as you will see pellicle formation on the capsule shell, which may resemble balloons, tentacles, or other formations. continued on p. 3

3 Proposed Changes to Testing Gelatin Capsule Shells with Cross-linking... continued Dissolution testing of these cross-linked products often leads to failure due to the restricted openings. As a result, USP Chapters <711> and <2040> historically have allowed the use of biological enzymes found in the stomach and intestinal region for dissolution testing pepsin in acidic ph and pancreatin in neutral ph media. These enzymes could be added when cross-linking was visually apparent or a dissolution test failed due to suspected cross-linking. The use of pepsin and pancreatin was partially successful in addressing failure due to cross-linking; however, neither enzyme is well suited for ph between An in-process revision of <711> is currently viewable in USP Pharmacopeial Forum 40(6). The revision contains modifications for enzyme use for capsule shells, with two additional enzymes specified for use in intermediate ph, and an increase in the amount of pancreatin for neutral ph. Other revisions include pre-treatment of a product in enzymes when the enzymes are not compatible with surfactants or other ingredients in the media. The deadline for public comment on revisions to <711> was January 31st, Dissolution Enzyme Selection Enzymes can be utilized when the dosage form fails to meet the acceptance-table criteria for a product. In such cases, dissolution would be repeated with the addition of enzymes to the dissolution media, either during the test or as part of a pre-soaking procedure. It is not required to fail through all three stages as long as evidence of cross-linking is observed as described in USP <1094>: Capsules Dissolution and Related Quality Attributes. Enzyme selection is dependent on the ph of the media being tested. For media ph 4.0, pepsin can be used in the amount of 750,000 units/l of dissolution media. For media ph > 4.0 and < 6.8, the enzymes papain or bromelain can be used at 550,000 units/l or NMT 30 gelatin-digesting units (GDU)/L of dissolution media, respectively. For media ph 6.8, pancreatin can be used at 2000 units/l, an increase from the previous limit of 1750 units/l. The determination of activity for each of the enzymes can be found in the Reagent Specifications section of the USP under each of their names. Cross-linking should be studied during dissolution method development for encapsulated products to determine the type and amount of enzyme that should be used. Forced cross-linking studies may be conducted by exposing the dosage form to high humidity or by spiking with formaldehyde or other cross-linking agents. Pre-soaking with Enzymes Enzymes have been known to become denatured or exhibit altered activity in the presence of surfactants and other ingredients. In these cases, the sample can be pre-soaked in the dissolution media without the presence of the surfactant. The pre-treatment time is counted as part of the total time of the dissolution run, and can occur either in the dissolution vessel or in another location, such as a beaker. The time of the pre-treatment is recommended not to exceed 15 minutes. The pre-soak can occur in a small volume of solution, which is then added to the rest of the dissolution media at the end of the soaking period; however, the total volume must be equal to the total volume required in the dissolution method. The pre-soak procedure, volume, mixing conditions, etc. should be determined as part of method development for each product. Prevention of Cross-linking Cross-linking is problematic in in vivo dissolution testing as well as in vitro. The most important thing in dealing with gelatin capsule shells is prevention through good formulation and packaging design. Using high-quality gelatin and choosing excipients less prone to forming aldehydes will reduce the occurrence of cross-linking. Packaging that protects the capsules from humidity and light can also slow the formation of cross-linking. Summary The addition of papain and bromelain as options for addressing cross-linking, as well as the increased allowable amount of pancreatin, should help address many of the challenges encountered with the previous USP procedure. As always, methods should be validated for use with and without enzymes when working with gelatin capsule shells in order to assure accurate and reliable dissolution testing. References USP Workshop on Dissolution Testing of Capsules, March 24-25, 2014, Rockville, MD. US Pharmacopeia <711> Dissolution, Pharmacopeial Forum 40(6), Nov-Dec, 2014 US Pharmacopeia <1094> Capsules-Dissolution Testing and Related Quality Attributes, Pharmacopeial Forum 40(6), Nov-Dec, 2014 US Pharmacopeia <2040> Disintegration and Dissolution of Dietary Supplements, Pharmacopeial Forum 40(6), Nov-Dec, 2014 US Pharmacopeia, Stimuli to the Revision Process: Use of Enzymes in the Dissolution Testing of Gelatin Capsules and Gelatin-Coated Tablets Revisions, Pharmacopeial Forum 40(6), Nov-Dec, 2014 US Pharmacopiea, Stimuli to the Revision Process: Collaborative Development of Two-Tier Dissolution Testing for Gelatin Capsules and Gelatin- Coated Tablets Using Enzyme-Containing Media, Pharmacopieal Forum 24(5), Sept.-Oct

4 Dissolution Source Book Triple Play For the first time, the Dissolution Systems Source Book has been released in three different formats: printed catalog, PDF, and now for an interactive version we are excited to call our Digital Source Book. While the PDF version is identical to our printed catalog, the Digital Source Book offers a wide variety of enhancements and features: Simple navigation, including a hyperlinked Table of Contents with thumbnails Digital Source Book Cover Embedded product videos and demonstrations Hyperlinks to brochures and white papers Product-specific ordering information Simplified Navigation Our Digital Source Book represents a more streamlined alternative to our printed and PDF catalogs. Over 190 pages have been condensed into 49 slides of interactive content, with an emphasis on delivering the information you need about our products in a more accessible way. Our new Contents page includes convenient thumbnails so you can navigate to any instrument or service visually. We have also included an easy-to-use search box that can be accessed on every page. Content is organized into digital chapters, allowing you to quickly advance through sections, based on your interest. Digital Source Book Table of Contents 4 Embedded Videos Want to see how a particular instrument or hardware/software feature works? Need to know how to validate filters or convert one of our dissolution apparatus for small-volume dissolution? Want to a watch a quick overview of the Dissolution Discussion Group, dissoguard, or Seminar Series, etc.? continued on p. 5 Digital Source Book Videos

5 Dissolution Source Book Triple Play... continued One way to see our instruments in action is to schedule a live Labcast HD demo with our team of dissolution experts (using the Contact Us link included on every slide of the Digital Source Book). Another way is to use the new embedded-video links in the Digital Source Book. Videos include segments on everything from individual features to full-length tutorials and demonstrations. Brochures and White Papers A variety of product brochures and white papers for our dissolution products can now be accessed directly from the slides of our Electronic Source Book. These resources expand on the content in the Electronic Source Book, providing much greater detail than is available in the printed catalog. Digital Source Book Literature Ordering Information While the page count has been reduced for the Electronic Source Book, ordering information has not been sacrificed. Context-sensitive ordering information is available on throughout the Digital Source Book that will take you directly to the pages in the PDF Source Book applicable to the content you are viewing. We hope you find this new way of interacting with our Source Book both useful and enjoyable. It is available today for viewing on your computer or any mobile device that supports Adobe Flash. Digital Source Book Ordering Information To get your copy, visit com/chem/dissolution-sourcebook or contact us at dissolution. hotline@agilent.com. 5

6 Tips and Tricks to Improve Your Dissolution Testing the medium is not necessary, correct for the volume change in the calculation. This means that an equivalence study one with media replacement and one without can be performed to demonstrate that dissolution results are not affected. In this case, we also need to ensure that the sink conditions remain satisfied as media is withdrawn throughout the experiment, and sufficient volume remains for adequate agitation. Media Replacement vs. Mathematical Calculations USP <711> states where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution media at 37 C. This statement appears to require replacement of media for all multiple-sample time point methods. And, while most dissolution manufacturers offer this feature as standard (as with Agilent s 850-DS Sampling Station) or as an option, it is important to understand if it is really necessary is it the most accurate way to account for the vessel volume lost due to sampling? Sink Conditions Having a volume of medium at least three times the volume required to form a saturated solution of drug substance. In fact, the full text of <711> directs to replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution media at 37 C or, where it can be shown that replacement of Performing such a study and demonstrating that a) sink conditions are maintained, b) adequate volume remains for agitation, and c) results are not affected, not only eliminates an additional step in the process but also removes a potential source of error. Mathematically, it is necessary to account for sample removed and, when necessary, replaced in % and mg dissolved calculations. However, when fresh media is added back to the dissolution vessel either manually or automatically volume accuracy is at risk. Minimizing volume removal and addition lessens the chances of inaccuracies or compounded errors. By simply adjusting the formula to fit your method you can save time, reduce steps, and improve overall dissolution test accuracy. Dissolution Sample Dilution: Physical vs. Optical Dissolution samples can occasionally present certain analytical challenges. These may arise from any number of sources, and may force exploration of sample dilution to improve analysis. Often, the first inclination is simply to dilute samples with fresh dissolution medium, which can be accomplished manually or automatically depending on the pumps and instrumentation available. However, in many cases this is not the most efficient or accurate way to achieve high-quality results. Manual sample dilution adds time to the overall dissolution process and introduces potential error related to contamination or inaccuracy. While automated dilution does save time, it can lead to volume inaccuracies caused by the inherent specifications of pumps used as part of this process. To meet the requirements of small volume sample dilution, each of these factors should be considered. continued on p. 7 6

7 Tips and Tricks to Improve Your Dissolution Testing.. continued One alternative method to achieve the necessary sample dilution one that does not require any modification to the sample itself is to optically dilute. This practice is most effective in an automated or online UV-Vis dissolution system where a variety of flow cells are available for sample analysis. By simply changing the path length of the flow cell and maximizing the linear range of the spectrophotometer, it is possible to increase the absorbance of the sample by however much is needed. This allows for analysis of a wide range of sample concentrations. Implementation of this approach saves sample preparation time by removing the physical dilution step. It also eliminates any chance of volume inaccuracies and helps ensure the integrity of the sample. Agilent s Dissolution Workstation Software Dissolution Workstation software provides control of up to four manual or semi-automated dissolution systems from a single workstation. Ideal for laboratories adhering to 21-CFR- Part-11 requirements, this easy-to-use software: Consolidates and maintains all your dissolution data in a secure, centralized database Agilent s Cary 60 boasts a linear range of up to 4 Abs and can utilize flow cells ranging from 0.2 to 10 mm in an online UV dissolution system. FREE for a Limited Time Discover Your Paperless, Compliant Lab Solution All Agilent dissolution orders containing any of the following instrumentation will now receive a complimentary copy of the latest Dissolution Workstation software: 708-DS or 709-DS Dissolution Apparatus Bio-Dis Reciprocating Cylinder (USP Apparatus 3) Reciprocating Holder (USP Apparatus 7) 850-DS Sampling Station Complies with the latest enhanced mechanical qualification (MQ) guidelines Integrates the new 850-DS and its automated cleaning cycle for long-lasting performance Accelerates failure investigations by monitoring the dissolution apparatus for vibration using the Instrument Module (IM) of the 280-DS MQS This offer won t last long, so take advantage of this excellent value and see how easy it can be to manage your dissolution methods and systems with one convenient, compliant solution. Contact your Agilent representative today for more details! Learn More Contact us at dissolution.hotline@agilent.com. 7

8 Learn more The information is subject to change without notice. Agilent Technologies, Inc Printed in the USA, February 1, EN