NQA/QC testing continues to evolve.
Every second of the day, someone is consuming a dietary supplement, whether in pill form, beverage, chew, etc. Consumers automatically take two things on faith—that the supplement will work as the label claims, and that it is safe; it won’t make them sick.
As new ingredients are being launched and others are refined or combined, this increasing ingredient inventory necessitates a wide variety of testing to ensure a host of factors. According to the U.S. Food and Drug Administration’s (FDA) cGMP (current good manufacturing practices) interim rule, “Consumers should have access to dietary supplements that meet quality standards and that are free from contamination and are accurately labeled;” and “The rule will give consumers greater confidence that the dietary supplement they use has been manufactured to ensure its identity, purity, strength and composition.”
Product quality problems that the rule will help prevent include:
• Dietary supplements that contain ingredients in amounts that are greater than, and less than, those listed on the label
• Wrong ingredient(s)
• Foreign material in a dietary supplement container
So you can see how crucial it is for your supplier and contract manufacturer to ensure testing facilities, operations and processes are up-to-date and are followed literally to the letter of the law.
Anurag Pande, PhD, vice president of scientific affairs with Sabinsa Corporation in New Jersey, emphasized, “Testing is a crucial component of GMP compliance and providing consumers with safe and effective products, which is the ultimate goal. If a facility does not have a well-designed testing lab with well-trained personnel, manufacturers can build the delay needed for third-party testing (and they need to make sure it’s a very good lab) into the production schedule. Is in-house more efficient? Absolutely. But every manufacturer must put emphasis of solid testing practices, no matter where it’s done.”
Analytical capability, Pande believes, serves as the backbone of product quality. The role of analytical testing is not limited to quality analysis of finished product, but it starts right from the selection of the raw material, hence in-house testing capability is important in order to provide a good quality material.
Although many manufacturers operate compliant testing labs, there is growing reliability on third-party testing as well. Joseph E. Mitchell, Jr., PhD, senior vice president, corporate quality with New Jersey-based Pharmachem Laboratories Inc., said he believes that, when possible, it’s best to utilize a contract manufacturer that has qualified cGMP laboratory testing instead.
The use of third-party laboratories is fairly common in the industry, he said. These labs are frequently chosen for several reasons: for smaller manufacturers/brand marketers that do not have any in-house testing capabilities, to avoid purchase of expensive analytical equipment that is needed for only a few sample analyzed infrequently and/or for short-term use to handle significant workload caused by increased customer demands.
“The use of these laboratories however is, generally, more expensive then in-house testing,” he noted. “Additionally, support of production may be delayed due to routine turnaround time. Expedited samples may double the routine costs normally incurred. Further, methods used by third-party labs are generally not verified for the submitted sample matrix which can lead to inaccurate results.”
Pande agreed, noting that a third-party or outsourced testing lab can not only delay the qualification process for raw material, but also the finished goods. Further, “in absence of robust in-house analytical testing facilities, production may not be able to put sufficient check points at critical steps of the processes, leading to failure of batches.” An in-house analytical laboratory has a significant role in processing raw materials through finished goods. Raw materials, especially of botanical origin, undergoes identification testing, and then raw material needs to be tested for actives, residual pesticide, heavy metal and microbial contaminants before it can be qualified for further processing. Once in production, each processing step is qualified as complete only after successful analytical tests. “All these processes are critically analyzed using the analytical tools. Deviations at any stage may affect the quality of the finished product,” he described. And those that are dedicated to the industry would have the knowledge of the process, the materials and at what point any material should be rejected.
Testing in House
On the flip side, Mitchell said, there are several benefits of in-house testing: the costs are generally lower, the lab analysts are aware of production demands and familiar with in-house verified methods that have been developed for specific formulations and respective matrices, and these analysts as employees have an ownership philosophy versus those at a third-party lab.
And, Mitchell warned, as a brand marketer, you are ultimately responsible for the quality of the product for sale. He explained that from a compliance perspective, third-party labs are considered an “extension” of the manufacturer submitting samples and therefore they must to be viewed and treated as an “internal” laboratory. “The company submitting the samples inherits the responsibility for qualifying any third-party laboratory for the sample it submits.”
Robust industry growth, characterized by new materials, new companies and new loyal consumers, creates the need for in-house labs to evolve and keep up. Into this mix, said Mitchell, is the increasing regulatory scrutiny of the FDA as the result of Part III GMPs. “We are finding that the technical competence of our customers is also continuing to increase,” he observed. Additionally, the once-common practice of relying only on COAs is now no longer allowable, and COAs are required to be verified via testing. “Testing of ingredients—and more specifically formulations—can represent significant challenges. The use of HPTLC, TLC, ICPMS and more sophisticated HPLC equipment is now a must,” he said.
Keeping Up With Demands
Sabinsa’s analytical labs are capable of performing not only the routine testing procedures for quality control but also serve as analytical R&D, according to Pande. Its analytical R&D lab is capable of identifying, isolating and characterization of new chemical entities, identifying and quantifying the active components of raw materials derived from nature. Plant extracts are frequently complicated and require analysis of active compounds present in a complex matrix, which demands a robust analytical system using modern hyphenated techniques such as HPLC-MS (high pressure liquid chromatography-mass chromatography). “In the last few years, keeping in pace with the developing technology and emerging knowledge about natural products, we have invested heavily in increasing analytical capabilities and continuous training of our analytical team to provide top quality extracts that marketers and their consumers expect from today’s marketplace.”
Testing procedures for materials and formulations are not static; they evolve and often do so to overcome challenges that may be present. One example is Sabinsa’s “R&D and analytical R&D have worked together to unravel an age-old myth of Saberry.”
Indian gooseberry, (Saberry), is one of the oldest fruits used in ayurvedic formulas like triphala. Pande explained that earlier studies suggested it to be very rich in vitamin C, which thus became used as the marker compound. Scientists at Sabinsa investigated the fruits from various sources and found that vitamin C may not be the predominant active constituent. During related investigational work, Sabinsa’s team, using medium pressure liquid chromatography, was able to isolate fractions showing maximum antioxidant potential; these fractions were later studied for the active constituents. “The isolated compounds were identified, using advanced spectroscopic techniques such as LCMS/MS and NMR, as beta glucogallin and mucic acid gallate, unique compounds occurring in Indian gooseberry fruits.” Botanicals, Mitchell agreed, represent the biggest challenge. “The use of HPTLC and TLC has long replaced the FTIR test for identity required by GMPs. The use of authenticated ‘botanical reference standards (BRM)’ and specific country of origin plant part and species are required. Economic adulteration has been reported for many botanical materials. If information is available for specific adulterants testing for these contaminates is now a must,” he reported.
Failures do occur, for whatever reason. When a material fails to meet an established specification, Mitchell said, it is required that the failure be subject to a very specific “out of specification (OOS)” investigation to determine the root cause and eliminate “testing into compliance.”
As testing continues to evolve, there are new analytics that are exciting. Recently, said Pande, Sabinsa acquired LC-MS/MS and GCMS/MS to estimate pesticide residues, residual solvents and other impurities in herbal raw materials as well as finished products. Using the latest model of LC-MS/MS, Sabinsa was able to authenticate its enzyme product (Digezyme) to be free from chloramphenicol contamination. “Comparable work is in progress for method development for analyzing other contaminants, such as ochratoxin, aflatoxins and other naturally occurring toxins in plant raw materials,” he reported. “Similarly, we developed the methods for estimating Poly aromatic hydrocarbons (PAH) in the raw materials using the latest model of GCMS/MS.”
For Mitchell at Pharmachem Laboratories, “Using UPLC/UFLC with a new ELSD (evaporative light scattering detector) one can analyze compound/ingredients without derivatization for amino acids, many carbohydrates and those where UV detection is not applicable. This results in time and cost savings and replaces the refractive index detector.”
Of course, Sabinsa and Pharmachem are only two of many suppliers and contract manufacturers that are deeply engaged in QA/QC analytical testing. When launching or reformulating with new ingredients or improved ingredients, always ask about how the ingredient and final formula is qualified for safe human consumption and meets your desired label claims. NIE