Bio-waiver is a term used for product approvals, particularly tablet/capsule, without requiring an in vivo (bio-equivalence/bio-availability) testing commonly required to establish the safety, efficacy, and quality of drug products. For bio-waivers, the requirement of bio-equivalence/bio-availability studies is substituted with in vitro drug release testing, commonly known as drug dissolution testing. It is, therefore, extremely important to note that drug dissolution testing is used as a surrogate of in vivo (bio-equivalence/bio-availability) testing. Stating otherwise is clearly not an accurate view or representation of the science.

In addition, regulatory, including pharmacopeial, requirements of in vitro drug dissolution testing are based on the assumption that if products met the dissolution test criteria, then products would be considered safe, efficacious, and of quality for human use. This is the reason that dissolution tests are often promoted as quality control/assurance tests for pharmaceutical products (e.g., tablets/capsules).

However, unfortunately, the dissolution tests (methods/testers) often recommended and used have never been qualified and/or validated for their intended purpose. The assessment of the quality of such products, using the recommended testers/methods, lacks scientific support and merit. Therefore, current practices of requiring bio-waivers lack scientific merit or credibility; thus, their requirements should be reconsidered.

As per a recent follow-up note from USP (link), it is stated that “It is known that the dissolution of USP Prednisone Tablets RS changes over time.” Is this a good thing?

In principle, if the tablets, or anything else, are not stable, then by default, these should not be used as a REFERENCE. How would their use as a REFERENCE be justified?

On the other hand, the new validity/expiry date has been extended for six months to December 31th, 2015. Will the tablets’ characteristics change gradually or will they change abruptly on December 31, 2015? If the dissolution characteristics’ changes are gradual, shouldn’t the Ranges be changed more frequently such as weekly, bi-weekly, or monthly, etc?

Some thoughts for consideration!

Last week USP once again, in a “surprise” announcement, informed that their current lot of Prednisone Tablets for PVT is not performing as expected, so its use is halted, at least for a while. The question is, is this a surprise or unusual occurrence? Anyone involved in drug dissolution testing, in particular PVT, would know that such occurrences are not unusual or new but becoming relatively frequent.

Anticipation is that USP might provide some information concerning the problem and hopefully the cause of such problems. However, past experiences show that such information may not be forthcoming; perhaps, some modifications to data presentation format and/or slight adjustments in Acceptance Ranges would be made with a claim that “all is well and good to go.”

Indeed, just today (a few days later from the previous announcement), it appears that the USP has released a continuation lot, with revised and adjusted Acceptance Ranges. Such scientifically poor practices from a reputed standard-setting organization such as USP are quite frustrating. USP should perhaps re-evaluate its practice of adjusting or re-adjusting the data “on the go”. Otherwise, manufacturers of the products should also be allowed to revise their products’ tolerances if their batches start giving different, or unexpected, sets of data!

On the other hand, the fact is that problems of PVT remain, i.e., frequent observance of PVT results falling outside the expected ranges reflecting high variability and unpredictability of the test. This high variability and lack of predictability in dissolution results are because of the testers (paddle and basket); however, unfortunately, USP Prednisone Tablets get the blame.

It is very important to note that to date, there has not been a single piece of evidence presented showing that indeed the failure of PVT is because of the Prednisone Tablets. On the other hand, many scientific studies have published showing that the high variability (or failures) is related to the dissolution testers (paddle and basket). Performance testing using Prednisone Tablets merely reflects the variability of the dissolution testers. It is just like if one’s computer monitor blacks out or flickers often, one has to assess separately whether the problem is associated with the monitor or the computer. If the computer is causing the problem, then adjusting or changing the monitor would not help. Similarly, in case of dissolution testing, adjusting or changing the Performance Tablets, and/or their Acceptance Ranges would not help. Therefore, USP must demonstrate that dissolution testers (paddle and basket) evaluated separately and independently from the Prednisone Tablets can provide predictable and relevant results i.e., these testers are validated and qualified to evaluate the dissolution characteristics of something or anything. Once this validation and qualification step has been accomplished, these testers should establish performance using Prednisone Tablets and/or actual drug products.

It’s hoped that the USP will use this latest miserable situation to address the well-known problem of the dissolution testers, not just by re-adjusting the Acceptance Ranges. Please consider providing a validated and qualified dissolution tester.

It appears that talking about the quality of drugs/pharmaceuticals and their products has become a fashionable topic, in particular with respected scientists and regulators. There appears to be clear fearmongering and a blame-game approach that is taking place to discuss the subject and perhaps to gain personal or professional recognition along the way. Such human elements are natural or expected; however, such emotional distractions should be managed, preferably set aside when it comes to science. This article is an attempt to provide a rationale and scientific point of view to highlight current difficulties in setting standards for developing and manufacturing quality drug products, in particular tablets and capsules.

Please click here for the article

It appears that talking about the quality of drugs/pharmaceuticals and their products has become a fashionable topic, in particular with respected scientists and regulators. There appears to be clear fearmongering and a blame-game approach that is taking place to discuss the subject and perhaps to gain personal or professional recognition along the way. Such human elements are natural or expected; however, when it comes to science then such emotional distractions should be managed, preferably set aside. This article is an attempt to provide a rationale and scientific point of view to highlight current difficulties in setting standards for developing and manufacturing quality drug products, in particular tablets and capsules.

Please click here for the article

These terms (safety, efficacy, and quality) are frequently used in literature, apparently without clear description and relevance. The lack of clarity and relevant use of the terminologies appear to cause confusion and seriously hinder the development and assessment of pharmaceutical products, such as tablets and capsules. It is highly unlikely that improvements in manufacturing practices of pharmaceuticals and their assessment, including associated regulatory standards and assessments, are possible without clearly explaining and objectively defining these terms. The purpose of this article is to help in explaining these terms, considering the underlying scientific concepts in order to facilitate improved product development and assessment.

Please click here for the article

These terms (safety, efficacy, and quality) are frequently used in literature, apparently without clear description and relevance. The lack of clarity and relevant use of the terminologies appear not only to cause confusion but also at present seriously hinders the development and assessment of pharmaceutical products, such as tablets and capsules. It is highly unlikely that improvements in manufacturing practices of pharmaceuticals and their assessment, including associated regulatory standards and assessments, are possible without clearly explaining and objectively defining these terms. The purpose of this article is to help in explaining these terms considering the underlying scientific concepts in order to facilitate improved product development and assessment.

Please click here for the article

During the last few days, to all those who wished me well, on LinkedIn and in person, for completion of my 30 years of service with Health Canada and retirement, and now initiating a new professional journey. I greatly appreciate your good wishes and the support you provided during the past few years. I am fully committed to continue providing such contributions in the future. I look forward to working with you to provide scientific ideas and solutions to problems and help bring quality products into the market faster and in a cost-effective manner.

To enhance more open scientific interactions, I am initiating a LinkedIn group (rDissolution) complementary to my blog (www.drug-dissolution-testing.com), as often people request a more open medium of interaction for my articles and blog postings which is not available on the blog itself. Please, join the forum (rDissolution) for more active discussions to learn and contribute.

I look forward to an exciting future, and if I could be of any assistance, please do not hesitate to contact me at principal@pharmacomechanics.com or moderator@drug-dissolution-testing.com.