Mechanical Calibration of Dissolution Apparatus—Stefan

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Dissolution testing was developed by pharmaceutical scientists to ensure that oral solid dosage forms do in fact dissolve and that one batch of tablets or capsules dissolves at the same rate as previous, approved batches. Dissolution testing helps ensure that tablets and capsules do not pass through the gastrointestinal (GI) tract intact without releasing the drug, and it also helps show that the dosage form is equivalent from batch to batch.

The 2 most common dissolution testers consist of temperature-controlled U-shaped glass vessels that are filled with liquid (usually purified water brought to acidity similar to that of the human stomach). In Apparatus 1 tablets or capsules are placed inside a rotating mesh basket that is lowered into the vessel. In Apparatus 2, a paddle is lowered into the fluid and the dosage is placed into the vessel, where the paddle rotates above it. The turning of the basket or the paddle inside the acidic liquid mimics the conditions in the stomach and GI tract.

At specified intervals analysts withdraw samples of the liquid and measure the amount of drug released from the tablets or capsules. Each drug has a specific drug-release profile, and by measuring this release and comparing it with established profiles analysts can measure dissolution profiles. In the US dissolution testing is performed according to the specifications in US Pharmacopeia (USP) General Chapter Dissolution <711> (http://www.usp.org/pdf/EN/USPNF/chapter711.pdf accessed 04 February 2010).

Studies have shown that dissolution profiles can be affected by several factors, including the temperature in the U-shaped vessel, vibration, irregularities in the interior walls of the vessels, variations in the alignment or speed of the basket or paddle rotation, and many others. These variables can significantly alter dissolution profiles and have sparked a debate about the relative values of mechanical calibration vs use of reference standards Basically, the question is: Can physical measurements of the dissolution apparatus ensure consistent results, or do analysts need to use certified reference standards (USP Prednisone Reference Standard Tablets) to determine if their equipment meets standards?

To address these questions the Food and Drug Administration (FDA) released its Guidance for industry: the use of mechanical calibration of dissolution apparatus 1 and 2—current good manufacturing practice (CGMP) in January 2010 (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198649.pdf accessed 04 February 2010). This guidance will help analysts, regulatory affairs professionals, and compendial scientists to conduct dissolution testing accurately and consistently.

FDA’s cGMP regulations for dissolution testing [21 CFR 211.160(b)(4) and 211.68] are satisfied by demonstrated compliance with <711>. At issue in FDA’s recent guidance is whether mechanical calibration is sufficient or whether analysts must compare the results of their equipment with USP Reference Standard tablets. The guidance recognizes the utility of both approaches and concludes “Either the Apparatus Suitability procedure in <711> [involving USP Reference Standard tablets] or an appropriately enhanced [mechanical calibration] method executed according to a written procedure will satisfy the CGMP requirement for calibration ...”

The guidance reviews recent publications about the relative merits of USP Reference Standards and calibration, citing several articles that draw attention to both the use of Reference Standards and some limitations of mechanical calibration. The guidance notes that an industry group advises manufacturers to use “enhanced mechanical calibration.” The final guidance avoids either extreme of mechanical calibration without use of Reference Standards or exclusive reliance on the latter without mechanical calibration. FDA also notes that neither approach is “as comprehensive or as stringent as those in the enhanced [mechanical calibration] procedure recommended in this guidance (for detailed specifications about enhanced mechanical calibration, see http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf accessed 04 February 2010). Finally, the guidance recommends that manufacturers pay particular attention to 3 aspects of mechanical calibration during dissolution testing: dissolved gases (which can cause bubbles to form on tablet or capsule surfaces) in the dissolution liquid, vibration, and vessel dimensions.

Overall, the guidance will give industry additional tools and increased confidence that the results of dissolution testing are accurate and reliable.

Stefan Schuber

BW 706 Tracey's 1st blog

The guidance I reviewed is the Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting To IRBs –Improving human Subject Protection. This is a final guidance that was released in January 2009. The guidance can be found online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079753.pdf . The target audience is anyone working on clinical trials of drugs, biological products or devices at investigative sites (ie, clinical investigator, and clinical research coordinator), IRBs, or sponsors (ie, clinical research scientist, pharmacovigilence department, site monitor). This guidance was written to clarify the requirements for reporting adverse events (AEs) that occur during clinical trials to the IRBs as outlined in Title 21 of the Code of Federal Regulations (CFR) part 56 (IRBs), part 312 (Investigation New Drug Application), and part 812 (Investigational Device Exemptions).
The primary purpose of the IRB is to protect the human subject participating in a clinical trial. To do this they evaluate the trial before it starts and during its conduct. To monitor subject safety they must be given the appropriate safety information such as reported AEs. However, even in the safest clinical trial many AEs occur and most do not constitute a safety signal. Prior to the guidance there was a lack of clarity regarding what types of AEs the FDA expected to be reported to IRBs. As a result, the volume of AEs reported to IRBs was overwhelming and thus, it was difficult for them to effectively evaluate significant safety issues.
In general, it is recommended that all unanticipated AEs reported during the clinical trials be reported to the IRB. The guidance defines an unanticipated AE as an event that is unexpected, serious, or would require a safety related change in the protocol or informed consent form (ICF). This is especially true if the event meets these criteria and is considered by the investigator to be related, or potentially related, to the drug, biological produce or device being studies.
In most cases a single occurrence of an event does not constitute an unanticipated event. For multicenter trials the sponsor is able to evaluate whether the event is unanticipated because they have the ability to review data from all study subjects. Therefore, it is recommended that the individual investigators conducting the study rely on the sponsor to report unanticipated AEs to the IRB. The sponsor would also be responsible for reporting a AE that was determined to be unanticipated to all participating investigators. Of course there are exceptions to every rule. Some events, such as liver damage, are considered serious events that are uncommon in the non-study population. It takes only one occurrence of an event like this to send up a red flag and be considered unanticipated. It is recommended in the guidance that these types of events be reported to the IRB even if it is the first time it occurred in the study.
In general, the guidance is very helpful although it does create a concern. While on one hand it makes sense that the sponsor, being the party that has access to all of the data, should be responsible for assessing if a AE is unanticipated. However, on the other hand, if a sponsor is inclined to hide unfavorable outcomes this reporting strategy opens the process up to bias and under reporting.

Test blog

Hi Everyone,
I think I have found the blog site but I never posted a blog before and wanted to post this one as a test run.

Linda

The Bayh Dole Act and the fate of research

While researching information for my Ethical and legal issues in Biomedical writing class on the Indian version of the American Bayh Dole Act, I came across a very interesting article which I would like to share with you.

The article can be found at: http://money.cnn.com/magazines/fortune/fortune_archive/2005/09/19/8272884/index.htm

The article makes for very interesting reading and touches on many different incidences and issues.

The article talks about how the Bayh Dole Act , which was passed in 1980 in the United States, wasn't looked upon as the savior of the fate of federally funded research in the United States. The Bayh Dole Act basically allowed grantee institutions conducting research with federal funds to patent and commercialize their inventions. Prior to the Bayh Dole Act federally funded inventions belonged to the government and a very few of these inventions ever reached the public.

With regards to the implementation of a version of the Bayh Dole Act in India, I have been asking myself many questions over and over again:

Will innovation be hampered if universities are allowed to patent, commercialize, and basically make money off of their inventions created with federal funds?

WIll it hamper basic scientific research?

Will it create a uncontrollable rat race amongst scientist in universities?

So many questions, but I haven't yet come to a conclusion in spite of weeks of research, questioning, pondering, and deliberation.

Moral Complicity

In searching the Internet for medical-oriented ethics organizations, I found the website for the American Academy of Medical Ethics (AAME). AAME's mission: "...to promote the interests of medical educators, medical practitioners and scientists, and to protect and promote the historic values that have provided the long-standing foundation for western medical care".

On AAME's website, I found the following article on moral complicity: http://cbhd.org/content/addressing-issues-moral-complicity-when-where-why-and-other-questions. The article poses many interesting questions that I'm not sure how to respond to. For example, should physicians take advantage of findings from research that they know was obtained under unethical conditions but will help their patients? The author, Robert Orr, MD defines moral complicity by using this example: Does person B (in this case the physician who uses the data) have any moral culpability by associating with the actions of person A (in this case the person who conducted the unethical research)?

Timing is important in determining moral complicity. If someone knows ahead of time that an unethical act is about to occur that they will later benefit from and they facilitate the unethical act in happening, they are morally complicit. Another factor in deciding if a situation is morally complicit is proximity. Orr discusses the example of someone who washes the windows of a medical office where abortions are performed. Wouldn't this person be less complicit than the doctor who actually performs the procedures? In all, Orr identifies 5 factors that should be examined to determine if a situation is morally complicit.

This article made me wonder how moral complicity coincides with, or differs from ethics? Are they the same?

Acres of Skin

In Acres of Skin (1998), Allen Hornblum discusses the experiments conducted on prisoners at Holmesburg Prison from the 1950's until the experiments ended in 1974. Unlike the subjects in the Tuskegee experiment, the prisoners were not exclusively African-American. Also unlike the Tuskegee trials, the Holmesburg Prison experiments did not focus on sexually transmitted diseases, but focused on dermatological experiments. Albert Kligman, MD was the dermatologist supervising the studies and shockingly likened the prisoners' skin to acres of fertile farmland. Prisoners were exposed to radioactive elements, hallucinogenics, and other toxins while Kligman tested various drugs, including what would become Retin A. For years after the experiments ended, prisoners still suffered from exposure to these chemicals.

In doing a Google search of Dr. Kligman, I found that he is on the faculty as Professor Emeritus at the University of Pennsylvania. He received his medical degree from Penn in 1947. "Contact sensitization" is listed as one his specialties, along with "cutaneous toxicology".

In interviews after the experiments at Holmesburg ceased, Dr. Kligman continued to defend his practices. In 2006, renewed interest in using prisoners for research resurfaced. Supporters proposed that the 1978 regulations forbidding the use of prisoners in clinical research be repealed but that the government add safety measures to prevent abuses. Dr. Kligman is quoted as saying that regulations that restricted prisoner use in clinical research "should have never been written in the first place" because of the gains that the research provided to the general population.

Where do we draw the line between achieving greater good and abusing individuals who are incarcerated, marginalized, or without representation?

Enrolling Ineligible Patients in Trials

I was not aware that physicians violate clinical trial enrollment criteria by allowing unsuitable patients to participate in trials.

In the 10/29/09 New York Times, Pauline Chen, MD writes about her ethical concerns that arose from wanting to enroll a very sick patient in a clinical trial. Dr. Chen explains that her patient, who was diagnosed with liver cancer and only had 3 months to live, just wanted to live long enough to see her first grandchild be born. Dr. Chen begins to think about enrolling the patient in a clinical trial for an experimental drug.

The article goes on to explain that many physicians are faced with this ethical decision: to maintain study enrollment criteria and protocol and therefore obtain information that can be generalized for all patients or to violate study rules by focusing on improving the health of one patient. If physicians do allow patients to be enrolled in clinical trials by not disclosing how sick the patient really is, not only are patients harmed, but the trials can be as well. In a survey of 700 physicians published in an bioethics journal, 90% responded that they are alright with violating trial enrollment criteria if a patient could benefit from the trial. Also surprising is that more than 60% of physicians said that they would break study rules to help a patient.

Findings indicate that the value of the relationship between the patient and physician is still high; physicians are willing to violate medical ethics to retain the patient-physician bond and help patients live longer, even if they may ultimately die from an uncured illness. Dr. Chen's patient was provided with the study drug without enrolling in the trial and she lived long enough to become a grandmother, dying a few days later.

This article and study further call into question clinical study results and medical ethics. Link to article: http://www.nytimes.com/2009/10/29/health/29chen.html