“Guideline on quality of oral modified release products”  (link). This is obviously a very important document and a must read. I think it will also help those who require freshening up their understanding of the role and requirements of drug dissolution testing in establishing the “quality” aspect of solid oral drug products.

I have received two or three queries on this topic in recent weeks. I am providing the response with a web-post so that others may benefit from my response as well. The current query is as follows (the name has been deleted and data has been blacked out to keep it confidential):

Qurey:

I read your many excellent articles which guide well the peoples who are new in drug delivery.
After reading a lot of literature on IVIVC, there is still a query in my mind as asked below:

Plasma drug level can be predicted from in vitro dissolution data by two ways:
1. Using convolution approach
2. Using IVIVC

I know how to predict plasma drug level using convolution approach but don’t know how to calculate from IVIVC.
In this context, I need your guidance.

Suppose I have established Level A IVIVC for a tablet formulation with following outcomes; Y = x.xxxX – x.xxx, R2 = 0.xxx.
Then I changed an excipient and did the dissolution testing for new tablet. The new dissolution data is attached. Its outcomes are as; Y = x.xxxX – x.xxx,   R2 = 0.xxx.
Now, how can I predict plasma drug level for this new tablets using previously established  IVIVC.

Thanking you in advance and regards

Response:

Please, note that plasma drug levels can only be predicted/estimated using the convolution method. IVIVC cannot be used to predict plasma drug levels. I realize that there has been significant promotion to this effect, but unfortunately it is not correct. Furthermore, IVIVC is also of limited, or of no use, during the product development stage, where prediction/estimation of plasma levels is required and the convolution method is the only option for obtaining the required results.

For further information on this topic the following articles may be of help.

http://www.drug-dissolution-testing.com/?p=1648
http://www.drug-dissolution-testing.com/?p=1643
http://www.drug-dissolution-testing.com/?p=833

The following comments are noted from one of my earlier posts, as reported in the FDA transcripts (link):

(1) “It is noted that literally 50 percent of the batches are thrown out every year because of dissolution failures, …”

(2) “There is no evidence that the products out there on the market are bad products. There is no evidence that the agency has done a bad job in serving as a surrogate for ensuring good quality products for the consumer. And, there is no evidence that industry is not focused on quality as an important attribute to manufacturing products.”

Putting these two together clearly shows that we are dealing with the problem of dissolution and not of products or industry? Please click here for complete post

People, who are not familiar with the recent history of dissolution testing and QbD may find the following two links useful. These links are for the transcripts of two FDA meetings (held in 2005) on the topic. These are quite long documents and worth reading every word of it. I have noted some of the quotes which may be quite interesting (shocking!). I am of the view that the main or one of the main reasons of starting QbD was to determine and address the issues of drug dissolution testing, in a systematic way based on valid statistical design and analysis (aka QbD). I wonder what happened to that objective and where have we been lost!!!

http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4137T1.pdf

http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4187T1.pdf

Some comments from the speakers:

Dr. Helen Winkle:

“There is no evidence that the products out there on the market are bad products. There is no evidence that the agency has done a bad job in serving as a surrogate for ensuring good quality products for the consumer. And, there is no evidence that industry is not focused on quality as an important attribute to manufacturing products.”

“I think this meeting brings us a step closer to understanding quality-by-design, especially as it relates to dissolution. I think it is really important. I think the whole topic today will really help open the door to us to move ahead in the area of dissolution, and I think we have learned a lot through our past meetings here.”

“The meeting topics that we have for this particular meeting are that we are going to talk about quality-by-design and control of drug dissolution.”

Dr. Moheb Nasr:

 “ … that there rate of drug release from solid oral dosage forms is a critical quality attribute.”

“ … that you approve of our approach of implementing quality-by-design in setting dissolution specification.”

Dr. Ajaz Hussain:

 “It is noted that literally 50 percent of the batches are thrown out every year because of dissolution failures, …”

“I see our colleagues from Health Canada here who have been criticizing this [dissolution test] for a long time. Thank you for coming, sir.”

QbD is often promoted as an approach for improving quality, enhancing efficiencies and reducing cost of the manufacturing of pharmaceutical products such as tablets and products. This article provides a critical assessment of this view. It is argued that the promotion appears to be an attempt to market of the expertise in statistical analyses. This distorted view in fact appears to be causing confusion and hindrance in accepting the QbD approach. A discussion is provided highlighting the underlying issues in this regard. Link for the article Please click here for complete article

It appears that there is serious and unfortunate confusion among the dissolution scientists/analysts which implies that the compliance and qualification/validation of apparatuses are one and the same or interchangeable. This is incorrect. The data obtained using apparatuses such as pharmacopeial paddle/basket, which usually are in compliance but NOT qualified/validated, have limited scientific validity and lack relevance to products’ attributes or qualities, as explained below:

A compliant apparatus means that it meets the required specifications commonly set by standard setting organizations (such as pharmacopeias e.g. USP <711>) for the manufacturing and operation of the apparatuses. On the other hand, a qualified and validated apparatus means that it can be used for its intended purpose to evaluate or assess, reproducibly, the characteristics of the product which in this case is drug dissolution testing. The qualification/validation step usually requires a reference (product) with known characteristics, established independently to the apparatus, which is to be qualified or validated.

It is generally assumed that if an apparatus is in compliance with the required specifications, then it is qualified and validated as well. This is often the case, but not with the dissolution apparatuses. As there is no reference product available with known dissolution characteristics, established independently, one cannot qualify and validate these apparatuses. If one cannot qualify and/or validate a dissolution apparatus, one also cannot determine dissolution characteristics of the test products either. Interpretation of dissolution results obtained from such apparatuses will be misleading at best and incorrect in general. Continue reading →

The in vitro drug dissolution tests, or simply dissolution tests, are conducted to evaluate potential drug release characteristics of a product in vivo or in the GI (gastrointestinal) tract. This in vivo dissolution is indirectly measured based on the observed plasma drug levels or profiles in humans. The drug levels in plasma provide the therapeutic (or toxic) effects thus representing the clinical outcome. Equal or similar drug levels in plasma are considered to provide equal or similar therapeutic effects and vice versa. Therefore, to have clinically relevant dissolution tolerances, dissolution results are to be linked to plasma drug levels. Please click here for complete article