Isnare Free Articles
Authors Contents [Add OpenSearch]
Distribute your articles to more than 6,000+ sites and 40,000+ email group publisher subscribers for as low as $2 / article...
Index  Article Directory  Medicines and Remedies
Embed this Article  
Bruce Rehlaender, Ph.D.

Bruce Rehlaender, Ph.D. x 30 articles

Liked the article? Consider buying me a beer!
$

Most Recent Videos Most Recent Videos

If there were a bar where all of the hip drug product formulators hung out at the end of a hard day of formulating, two things would be certain, the beers on tap would be from breweries like Avery, Greenflash, and Dogfish Head rather than Coors, Miller, and Anheuser Busch, and all of the jokes would be about discovery guys. We formulators would pick on the discovery guys in part because deep down inside we realize they are smarter than us and get more dates than we do and in part because they make our lives miserable, and they think that DMSO is a formulation. Just as likely in this bar is that no one would dare challenge out loud the sanctity of our bible, the FDA Inactive Ingredients Guide, for fear of being beaten up out back by a bunch of hooligan formulation zealots.

Just in case there are any discovery guys reading this, the Inactive Ingredients Guide (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm) is a list of (supposedly) all excipients used in marketed drug products listed by route of administration and level in the formulation. For a long time this was a pdf document that hadn’t been revised since 1996, but more recently, the Agency has maintained it as a searchable database that is presumably updated as new drug products are approved. We rely on it to know what has been safely done already so that we don’t come up with a formula that provides great solubility, stability, and bioavailability but does irreparable damage to the patient. And just as importantly, we rely on it so that when our boss or sponsor asks us if that excipient is precedented, we can point to the list and say “there it is; FDA said it’s okay.”

While the Inactive Ingredients Guide is certainly a useful reference, and we can be grateful to the Agency for providing it to us, there are a number of pitfalls with relying on it too heavily, and without trying to pick a fight, I want to point some of these out:

• First and foremost, the guide is only a list of excipients that have been used and not a list of excipients that are allowed in a particular type of dosage form. If an excipient is not on the list, it may mean that it is harmful, but it more likely means that no one has had the guts to venture off The List and use it. For example, anyone who has ever worked in inhalation can tell you, sometimes rather emphatically, that phosphate buffer cannot be used in nebulizer formulations, but I have yet to find anyone who can tell me why not. Even the pulmonary division at CDER may be unclear on this point, as I have seen phosphate buffered saline used as a nebulized placebo in some FDA-approved clinical trials.

• Just as importantly, the fact that an excipient is on the list for a particular route of administration does not necessarily mean that it is safe. Paclitaxel has been formulated with high levels of the PEGylated surfactants, Cremophor EL and Polysorbate 80, both of which are known to cause anaphylaxis in susceptible humans and in pretty much all dogs. The FDA accepted these formulations because they were the only thing that worked for a drug that isn’t used unless it is the only thing that works. It doesn’t mean you can go crazy with the Cremophor in an injectable formulation of ibuprofen.

• Even if a drug is on the list for a particular route of delivery, the details of administration never seem to match the target at hand. Looking up an excipient in the database is just the first step in assessing whether it is precedented. One need next dig out package inserts for the actual drug products it is used in and determine whether the level of the excipient and the site, rate, and duration of administration as well as the dosing frequency and period of dosing are sufficiently similar to the intended use at hand. Since the names of the drug products are not listed (or even hinted at) in the database, this is best done by searching the name of the excipient and the route of administration on a package insert-providing website such as http://RxList.com or http://Drugs.com. If you are doing anything more complicated than a bolus injection or an IR tablet, don’t count on finding an exact match to what you want to do.

• Since the list includes only approved products and since it takes so long to get a product approved, the fact that an excipient is not on the list does not mean that it has not undergone extensive clinical testing and been found to be safe. Only a few years ago many of our clients shied away from using hydroxypropyl-beta-cyclodextrin (HPBCD) even in Phase 1 formulations since the only two cyclodextrin-based formulations on the list used the sulfobutyl ether (Captisol®). The four HPBCD-containing products currently on the list would likely have been through most or all of their Phase 3 trials at the time.

• Contrary to what some may believe, the database is not complete. When performing the abovementioned searches on package insert websites I almost always come up with a few drug products that are not included on the FDA list.

• Another more trivial concern with using the database is that you really need to be sure that you know the correct name of whatever you are looking for. For example, if you do a search on ethanol, you will come up with a relatively short list of ethanolamides and ethanolamines but nothing that would taste good in your punchbowl. You need to search on alcohol if you want to know where the strong stuff is.

What are the disadvantages of using an excipient that is not precedented? From the regulatory perspective, the FDA is only interested in whether the overall drug product is safe and efficacious and well enough controlled to be consistent from batch to batch. They are not the ones telling us we can only use what is on their list. Nonetheless, besides pleasing your boss, there are some distinct advantages to sticking to what is tried and true:

• The prior use of an excipient in a similar formulation amounts to a clinical history, just as a drug that has been used before has a clinical history that it allows it to slide through on an ANDA or 505.b.2. Every drug product is its own entity and is judged on its own merits regardless of what excipients it contains, but having a precedent substantially reduces the risk of an unanticipated problem and makes for easier writing in the Pharmaceutical Development section of an NDA.

• The fact that an excipient has been used for the same route of delivery in an approved product means that there is a Drug Master File on it as well as a supply that is appropriate for the use. A little carnauba wax might be just the thing to brighten up your injectable formulation, but you might be hard pressed to find an endotoxin-tested grade.

The main reason we formulators have such a hard time getting dates is that we are inherently boring people. While the discovery guys are creating spanking new molecules for novel targets, we are stuck in our dingy labs searching the shelves for those same old bottles of HPMC or PEG or lactose. We tend to blame our conservative ways, directly or indirectly, on the FDA, but it is really not they who are holding us back. In most cases it makes sense to stick to what we know, but I wonder how often safer or otherwise better formulations have been overlooked simply because they were not sufficiently similar to what had been done before.

As some final advice for my fellow formulators:

1. Never forget that all those sexy discovery, pre-clin, and clinical people are useless without us.

2. As to the title of this piece, I would certainly not advise you to try bacon fat as an excipient, especially if you are trying to reformulate Lipitor, but if there were a demonstrated safety or efficacy advantage and you had a well-controlled supply, there is no legal reason you could not throw in a bit.

3. If you are thinking about a novel excipient, be bold and stand your ground. Don’t let anyone tell you that you can’t use it just because it is not on some list. Go ahead and throw in a sodium rather than a potassium salt or a sulfate rather than a chloride. Be the first on your block to put whatever crazy new thing Gattefosse comes up with into an injectable. Use phosphate in a nebulizer or black pepper extract in a nasal spray. Whatever you put in, I promise I will find a way to use it too. Once you get it on The List.

Find more articles like this one by searching for "PharmaDirections Formulation Development Blog".

Rate this article:
Bruce Rehlaender, Ph.D., Principal, Formulation Development, PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We direct development for virtual biotechs.
Important NoticeDISCLAIMER: All information, content, and data in this article are sole opinions and/or findings of the individual user or organization that registered and submitted this article at Isnare.com without any fee. The article is strictly for educational or entertainment purposes only and should not be used in any way, implemented or applied without consultation from a professional. We at Isnare.com do not, in anyway, contribute or include our own findings, facts and opinions in any articles presented in this site. Publishing this article does not constitute Isnare.com's support or sponsorship for this article. Isnare.com is an article publishing service. Please read our Terms of Service for more information.

Most Recent Articles

HPE0-S46 Test Certification

An Article by Brent Fowler in Computers and Technology

11 hours ago

Question: 1An architect has designed an HPE BladeSystem with Flex-10D Virtual Connect that connects to HPE 5830 switches The architect needs to ensure that the solution simplifies the customers campus Ethernet. Which additional HPE technology should the architect recommend to the customer. A. Intelligent Resilient Framework (IRF)B...

Boosting the Curbside Appeal of Your Business

An Article by Clean Sweep in Business

12 hours ago

Running a business requires a bit of insight. In order for you to get your company ahead, it is a good idea to consider the many different ways that you can appeal to your customers. For example, the way that your business appears to the outside will play a huge role in your continued success. An establishment is in a state of disrepair is less likely to be patronized than one that has a clean appearance from the exterior...

HPE0-S46 Preparation Material

An Article by Dennisng Ng in Marketing

13 hours ago

Question: 1An architect has designed an HPE BladeSystem with Flex-10D Virtual Connect that connects to HPE 5830 switches The architect needs to ensure that the solution simplifies the customers campus Ethernet. Which additional HPE technology should the architect recommend to the customer. A. Intelligent Resilient Framework (IRF)B...

Instagram as a Shopping Platform

An Article by Dave Furness in Business

13 hours ago

Howdy. From being a media-sharing app for selfies and anything visually appealing, Instagram is branching out into the eCommerce field. It will soon roll out a shopping feature which online retailers and shoppers will find very convenient. The social giant is pretty much aware how mobile commerce could overtake PCs in two years' time or even earlier, hence it wants to be one of its cornerstones...

ACE-A1.2 Preparation Material

An Article by Brent Fowler in Computers and Technology

14 hours ago

Question: 1On EOS 4. 13. 1F, which of the following statements are true in regards to Aristaís Tap Aggregation feature. A. Tap ports are send only. B. Tap ports are receive only. C. Tool ports are send only. D. Tool ports are receive only. Answer: DQuestion: 2Where does Aboot look for the boot system image at boot time...

Reach Out For Best Mens Herbal Healthcare Products of Ayurveda For a Fit and Bouncy Life!

An Article by Kairali P in Wellness, Fitness and Diet

14 hours ago

Since centuries, the wise men in the world have pooled their energies and knowledge to understand the processes that determine human health and its parameters with the objective of optimizing the health benefits for all. We also developed medicine systems through our knowledge of indigenous herbs and products of relevance to our health and wellness...

How to Improve Mental Health Naturally

An Article by Adrian Joele in Wellness, Fitness and Diet

15 hours ago

Mental health problems, like depression and anxiety are experienced by more people worldwide than any other physical disorder. According to predictions from the World Health Organization, by 2020 depression will cause greater disability than any other mental or physical disorder. This is a severe problem and it is common sense that we find effective solutions for these problems...

ACE-A1.2 PDF Download

An Article by Dennisng Ng in Computers and Technology

16 hours ago

Question: 1On EOS 4. 13. 1F, which of the following statements are true in regards to Aristaís Tap Aggregation feature. A. Tap ports are send only. B. Tap ports are receive only. C. Tool ports are send only. D. Tool ports are receive only. Answer: DQuestion: 2Where does Aboot look for the boot system image at boot time...

Ultimate Guide to Getting Fit With Exercise Bikes

An Article by Workout Workshop in Wellness, Fitness and Diet

17 hours ago

As much as we want it, following a fitness regime is not easy. Maybe this was the year, you swore to get back in shape and dedicate some quality time towards spirituality, but you couldnít. It is not as effortless as it seems. Also the constant worry of busting on the budget while buying fitness gear is a problem...

Live the Deluxe Life With La Limo and La Party Bus

An Article by Vikram KR in Travel

17 hours ago

In this modern era, people like to enjoy luxury to the fullest according to their capability of affording. Parties are very common not only among the young generation but among the elder members as well. Life has become much more extravagant and people are now more interested in indulging in the deluxe luxuries that the world has to offer...

Should You Transfer Your Home Loan in the Present Scenario?

An Article by Anamika Verma in Finances

17 hours ago

Banks have seen a sudden spiral increase in the total number of deposits done by customers. As a result, interest rates have been reduced by all NBFCs and credit banks. If you own a Home Loan presently, you might be contemplating a Home Loan transfer to make the most of the prevalent low rates. These guidelines will prove to be useful for you...

352-001 PDF Training Guides

An Article by Dennisng Ng in Internet

18 hours ago

Question: 1A company plans to include Nonstop Forwarding and Bidirectional Forwarding Detection as a part of their network redundancy plan. In which two ways do NSF and BFD work together when different hardware platforms are compared. (Choose two. )A. During supervisor engine or routing engine failover, the NSF feature will always ensure that the BFD at the peer router will not trigger a link down independent of the used hardware platform...

Latest VCP6-DTM Certification Exam 2V0-651 Practice Test

An Article by Kruis Barry in Education

20 hours ago

Our Latest VCP6-DTM Certification Exam 2V0-651 practice test is the best option for students because we are very straightforward and our products are very simple to use. We offer special offer on 2V0-651 Value Pack that contains PDF and Practice Test Software. In short, you will have guaranteed Latest VCP6-DTM Certification Exam 2V0-651 practice test in affordable price...

Latest VCP6-DTM Exam 2V0-651 Study Guide

An Article by Kruis Barry in Education

21 hours ago

Passcert Latest VCP6-DTM exam 2V0-651 study guide are recent and updated on regular basis, giving you with the highest 2V0-651 exam standard. Start your way to 2V0-651 success by purchasing Passcert high quality Latest VCP6-DTM exam 2V0-651 study guide. 2V0-651 download is maintained and run by a team of IT experts who administer and give a diversity of useful material, which will help the students to achieve the success...

200-710 Study Guides

An Article by Dennisng Ng in Business

2 days ago

Question: 1What is the difference between the spaceship operator () and the strcmp() function. A. There is no difference in functionalityB. strcmp() returns a Boolean value, the spaceship operator a numbeC. strcmp() does a case-intensive comparison, the spaceship operator does notD. The spaceship operator returns -1, 0 or 1; strcmp() may return any integeAnswer: DQuestion: 2Which of these error types may be handled by a user defined error handler function...

MLA Style Citation:
Ph.D., Rehlaender, Bruce "Pharmaceutical Formulation Development Series: Why Canít I Use Bacon Fat In My Drug Product Formulation?." Pharmaceutical Formulation Development Series: Why Canít I Use Bacon Fat In My Drug Product Formulation?. 08 Apr. 2013 Isnare.com. 29 Mar. 2017 <https://www.isnare.com/?aid=1830188&ca=Medicines+and+Remedies>.
APA Style Citation:
Ph.D., Rehlaender, Bruce (2013, April 08). Pharmaceutical Formulation Development Series: Why Canít I Use Bacon Fat In My Drug Product Formulation?. Retrieved March 29, 2017, from https://www.isnare.com/?aid=1830188&ca=Medicines+and+Remedies
Chicago Style Citation:
Ph.D., Rehlaender, Bruce "Pharmaceutical Formulation Development Series: Why Canít I Use Bacon Fat In My Drug Product Formulation?." Pharmaceutical Formulation Development Series: Why Canít I Use Bacon Fat In My Drug Product Formulation? Isnare.com. https://www.isnare.com/?aid=1830188&ca=Medicines+and+Remedies
Copy and paste the code below to embed this article:
<a class="embedly-card" href="https://www.isnare.com/?aid=1830188&ca=Medicines+and+Remedies">Pharmaceutical Formulation Development Series: Why Canít I Use Bacon Fat In My Drug Product Formulation?</a> <script>!function(a){var b="embedly-platform",c="script";if(!a.getElementById(b)){ var d=a.createElement(c);d.id=b,d.src=("https:"===document.location.protocol?"https":"http")+"://cdn.embedly.com/widgets/platform.js"; var e=document.getElementsByTagName(c)[0];e.parentNode.insertBefore(d,e)}}(document);</script>