Breakdown

December 17, 2009
Walter Friesendorf

The next phase of dietary supplements Current Good Manufacturing Practices (CGMP) audits is now underway for manufacturers. Conscientious manufacturers and packagers are taking advantage of a vast host of consultants, industry experts, webinars, seminars, mock inspections, and CGMP-compliant programs to armor themselves for an anticipated visit from government inspectors. However, ensuring quality is not merely about satisfying CGMP audits.

It may sound like an obvious statement, but product efficacy-and very importantly, a tablet's disintegration time-significantly affects sales and customer satisfaction. A good example of a company that understands this is NBTY, whose Boca Raton, FL, facility was the first to undergo a dietary supplements CGMP audit in August 2008. During the audit, the facility's quality-assurance excellence was acknowledged when the lead FDA inspector announced, after completion of the audit, that the facility was in full compliance with the new CGMPs.

In particular, NBTY was lauded for its excellent Master Manufacturing Records. Part of NBTY's records contained, among other specifications, disintegration end-times for each and every tablet and capsule manufactured at the Boca Raton plant. All disintegration tests described in NBTY's records and standard-operating test procedures either met or exceeded relevant United States Pharmacopeia (USP; Rockland, MD) disintegration guidelines. Adhering to USP recommendations turned out to be an important FDA audit criteria.

IN ITS CGMP RULES (21 Code of Federal Regulations, Part 111, page 175, part 13), FDA acknowledges that bad disintegration time is indeed an example of a product complaint regarding dietary supplements. In response to comment number 47, on page 177, the agency indicates that complaints about disintegration time could indicate a problem with production and process control that may affect the quality of a dietary supplement. FDA's response to comment 183, located on page 391, notes that nothing in FDA's final rule precludes manufacturers from establishing disintegration specifications. However, there must be scientific test data to support such specifications.

Disintegration testing standards are modeled in accordance with USP-NF General Chapter <2040> for dietary supplements. NBTY often exceeds USP and FDA standards. An example of exceeding official standards is qualifying all incoming hard gel capsules, excipients, and ingredients for their disintegration times. According to NBTY's Boca Raton quality-assurance manager, Robert Feldman, it is not unusual for any given batch of empty hard gel caps or raw materials to fail NBTY's disintegration standards.

Pioneering Secondary Testing and Customer Satisfaction

Another example of exceeding USP and FDA standards is New Spirits Naturals (NSN; San Dimas, CA), a marketer of dietary supplements founded nearly 28 years ago by Larry and Debbie Milam. The company's focus is on quality, efficacy, and customer retention. In early 2008, NSN purchased a USP-compliant, two-basket, semiautomated disintegration tester to monitor incoming solid-dose products supplied by contract manufacturers, as well as to aid in the development of new products.

A QUICK GUIDE TO DISINTEGRATION TESTERS

THE DISINTEGRATION TESTER was first described by U.S. Pharmacopeia (USP; Rockville, MD) in 1950. It consists of a basketlike assembly housing glass tubes and a motor-driven device for raising (upstroke) and lowering (downstroke) the test sample–containing basket into a test fluid at a constant frequency. With the exception of the use of modern electronics and other modern materials, the overall design and tester specifications haven't changed.

There are two types of USP-compliant disintegration testers. The most commonly used tester is the basic semiautomated tester, also referred to as a manual tester. The second type is the fully automated tester. Both types of testers are available in one- to six-basket models, depending on the manufacturer. A detailed description of the basket and associated apparatus can be found in USP-NF General Chapters <701> and <2040>.

With semiautomated testers, you can set a predetermined test time-for example, 30 minutes-and press the start button. The tester will turn off when the 30 minutes elapses. Fully automated testers measure the progress of disintegration and/or the end-time for each tube, and shuts down the test station when test samples in all of the tubes in the basket have disintegrated.

Test baskets are available with six or three tubes. The tubes in a six-tube basket can accommodate products up to about 0.75-in. long, while the tubes in a three-tube basket will accept products measuring up to approximately 1.3-in. long. If you manufacture large-animal veterinary products, a bolus basket with one tube is also available. All baskets are interchangeable and can be used in a mixed configuration if so desired.

Semiautomated testers are available in two types: those with a bath (water jacket) for maintaining temperature, and bathless units that heat the test beaker directly. There is another type of bathless tester that simply immerses the test basket directly in a large temperature-controlled reservoir of test solution. This particular type of tester also eliminates the need for individual beakers for each basket and is popular with six-basket semiautomated testers.

Fully automated testers are also available in bath and bathless models. Some automated units only record the disintegration end-time for each tube in the basket, while other disintegration testers record and plot the disintegration curve for individual tablets or capsules with each upstroke of the basket.

One important feature to look for when buying a basic semiautomated disintegration tester is independent stations. This versatile feature allows you to set different test times for each basket, rather than have all the baskets programmed for the same time period. Fully automated recording testers use either mechanical contact, magnetic disks, or inductive technology to measure and record the disintegration curve and end-time. Inductive technology is the most reliable and consistent measurement indication method, as well as the one with the highest conformity to both USP and European Pharmacopeia guidelines.

Disintegration testing can also be contracted to an independent test laboratory. The going rate for a basic end-time test is $125 to $175 an hour, usually with a one-hour minimum. The rate for plotting detailed disintegration curves would probably be higher.

Larry Milam says that he is very positive about the benefits that secondary testing has introduced to his firm. Since the inception of disintegration testing, coupled with feedback from NSN to its suppliers, customer complaints associated with disintegration times have ceased, he says.

Stringent quality and customer satisfaction matters related to the intricacies of marketing products in 28 counties led NSN to recently begin manufacturing its own hard gel products. The selection of a hard gel supplier entailed a two-month search and lots of disintegration testing.

Milam said that he also learned that the disintegration characteristics of hard gel capsule products may be adversely influenced by the makeup and quality of a capsule's ingredients. NSN now tests all incoming empty gel caps and raw materials to ensure they meet international disintegration standards. As Milam says, "Customers have so many choices and opportunities, the risk of customer loss is too great not to do disintegration testing."

Ingredients and Excipients: Disintegration's Achilles' Heel

A select number of dietary supplement manufacturers and raw materials suppliers realize the value of knowing the precise disintegration characteristics of their products. Precise characteristics refers to the actual disintegration curve, not just disintegration end-times. Disintegration curves are measured using automated recording disintegration testers that are capable of plotting the disintegration progress with every upstroke of the basket, or about one measurement every second. (Learn more about how disintegration testers work, in the sidebar.)

Germany-based JRS Pharma supplies excipients on a global level to many major pharmaceutical, nutritional, and contract manufacturers. JRS Pharma principal scientist David Schaible, based at the company's Patterson, NY, facility, relies on an inductive recording disintegration machine to assist JRS Pharma customers in developing formulas, with the goal of achieving optimum disintegration characteristics.

Schaible advises that lubricants are highly hydrophobic and are responsible for 90% of all formulation problems that he encounters, including problems with disintegration and dissolution. He also says, "A proper balance of disintegrants and lubricant in any formulation is necessary to ensure proper tablet disintegration." To avoid problems, he suggests conducting disintegration tests when a change in the level, type, or manufacturer of disintegrants or lubricants is made.

The quality-assurance managers and senior formulation scientists interviewed for this article also all agree that an often overlooked contributor to disintegration properties is active dietary ingredients. The hydrophobic properties and particle size of active dietary ingredients both play a role in influencing disintegration characteristics. Therefore, testing the impact that raw materials have on disintegration is critical in maintaining quality standards-especially when you substitute ingredients, change formulation levels, or source new suppliers.

Benefits Down the Line

Possessing a scientifically valid knowledge of your product's disintegration time-and possibly even knowing the disintegration curve of all of your solid-dose products, including hard and soft gel capsules-can help companies manufacture superior, high-quality, and more-consistent products; provide more-professional and informed customer service at both the consumer and contract level; help to establish and maintain a competitive edge; and assist in optimizing production efficiencies.

 

CASE STUDY: DISINTEGRATION TESTING OF A DIETARY SUPPLEMENT

THE DISINTEGRATION TESTS illustrated in the accompanying graphs were conducted by Dr. Schleuniger Pharmatron (Manchester, NH) using a fully automated recording disintegration tester. Disintegration progress was measured with each upstroke of the basket, or about every second, using inductive technology.

The product tested was a multivitamin, mineral film–coated oblong tablet. The USP disintegration guideline for film-coated tablets is 30 min. Test tablets were chosen randomly from a 90-tablet bottle.

Test 1
Disintegration times for the tablets ranged from 13 min and 26 sec to 20 min and 38 sec. Two tubes, 1 and 3, were not tested to completion, because it became obvious that the tablets in these tubes were going to fail. The tablet mass remaining in tubes 1 and 3 at the termination of the test, after 29 min and 16 sec, was 24% and 27% respectively. The test failed, requiring the testing of 12 additional tablets.

Test 2
Disintegration times ranged from 11 min and 2 sec to 17 min and 26 sec. All tablet disintegration times met USP guidelines.

Test 3
Disintegration times ranged from 18 min and 0 sec to 28 min and 26 sec. All tablets met USP guidelines.

Observations and Comments
USP specifications simply state to observe tablet disintegration at the end of 30 min. However, I believe that this criteria falls short by not giving disintegration time ranges or addressing fluxuations and inconsistencies within the specified time span.

According to USP specifications, however, this batch passed the disintegration test. Only 2 tablets out of 18 took more than 30 min to disintegrate. If three tablets had failed, however, which was nearly the case, the entire batch would have had to be reworked or discarded. However, the exceptionally wide range of disintegration times indicates that there could be a potential quality problem with this particular batch of tablets.

While not desirable, a wide range and fluxuation of disintegration times is not unusual. In this test, we had a low disintegration time of 11 min and a high disintegration time of more than 30 min, for nearly a 300% spread, with 50% of the tablets disintegrating in the 17- to 22-min range.

I have seen similar tablets disintegrate within a minute or two from one another and can't help but wonder if the quality of the tablets tested for this article could be improved. Do the tablets that disintegrated in the 11-min range have the same potency and efficacy as the ones that disintegrated in more than 30 min? What is the cause for such a wide variation in disintegration times-poor blending, raw materials, or something else?

If you have only a basic disintegration tester, every so often, and especially during formulation development, it might pay to divide disintegration testing into stages. For example, performing three 10-min progressive tests, or six 5-min progressive tests,for a 30-min USP specification will give you some insight on the disintegration curve.

Originally, I wanted our test to show the disintegration curves for both soft and hard gel caps, as well as for tablets. We conducted the tests; however, the capsule results were so consistent that we decided to focus exclusively on the tablet test results. The soft gel caps, 1000 mg in size, took between 6 min and 22 sec to 6 min and 54 sec to disintegrate. Hard gel caps, size 2, took between 3 min and 0 sec and 3 min and 36 sec to disintegrate.

Walter Friesendorf is a certified clinical nutritionist and the national sales manager for solid-dose tester manufacturer Dr. Schleuniger Pharmatron. He can be reached at waltf@pharmatron.com.