Paula Brown, Catherine Rimmer11.01.10
I have always loved a good puzzle, from the classic jigsaw, a good “who done it,” to, yes, even a spectrometry-assisted structure elucidation. Regardless of the type of puzzle, the principle is pretty much the same—find the corners or key parts, build the framework and try to see the whole picture, not just the individual pieces. The puzzle I have been trying to work through over the last two years in this column is product quality within the context of the dietary supplement GMP regulations.
Recently, on the topic of GMP, a veteran FDA inspector described a manufacturing facility as a large box. Now when I hear “box” I start thinking black box, particle in a box and that box which holds the cat. This is not an abstract mystery-type box, though; he said the essence of GMP is that a manufacturer must know everything that goes on inside the box. Further, the manufacturer must demonstrate to inspectors that not only does he know what is going on in the box, but that he has total control over everything in the box.
He went on to tell the tale of a food facility that suffered from frequent shutdowns due to microbiological contamination. During the course of an inspection aimed at finding the source of the microbes, the inspector requested the blueprints of the factory. Alas, there were none, and the manufacturer was forced to start dismantling his production facility in order to find out and regain control of what was happening inside his “box.”
Ultimately, the problem was identified as unsealed hollow table legs on the production floor serving as reservoirs for bacteria. The manufacturer was unaware of the hollow legs, which could not be easily cleaned and disinfected, a GMP violation itself. They got off lightly in this case by replacing the table legs, but careful scrutiny of blueprints before production began could have avoided multiple shutdowns and partial dismantling of the plant.
While many joke that “GMP” stands for “Great Mountains of Paperwork,” this is not just a tedious exercise. The truth is that through the process of putting together that documentation the manufacturer will learn in great detail everything that is going on in their facility and will identify the critical operations for maintaining control. The essence of the GMP: knowledge and control.
Now here is where the puzzle gets tricky. The responsibilities of the manufacturer go far beyond its facility or “box.” In fact, the GMPs make many non-manufacturing operations the responsibility of the manufacturer, which means they must also know and control what is in other people’s boxes. Keeping this in the context of product quality and the GMP, let us consider that part of a manufacturer’s box is the contract analytical laboratory.
The Lab
Past columns have addressed the role of Certificates of Analysis (November 2008) and Contract Analytical Laboratories (January/February 2009) in GMP, and what it always comes down to is that product specifications must be set and manufacturers must have tests to demonstrate that those specifications are met. Specifically, Section 21 CFR Part 111.320 (“What Requirements Apply to Laboratory Methods for Testing and Examination?”) says: (a) You must verify that the laboratory examination and testing methodologies are appropriate for their intended use; and (b) You must identify and use an appropriate scientifically valid method for each established specification for which testing or examination is required to determine whether the specification is met. In other words, the laboratory testing cannot be a black box where materials go in and the CofA comes out.
How can you document to inspectors that you know what is going on inside the laboratory box, especially if those operations are not within your facility?
When it comes to ensuring quality results are generated from a laboratory, there are three key elements of laboratory quality assurance that are generally accepted as essential. These include: accreditation (involving third party auditing), use of validated analytical methods and participation in laboratory proficiency testing exercises.
The GMPs are very clear that you need to demonstrate that methods employed are appropriate for their intended use and the ‘Why’ and ‘How’ of method validation has been addressed previously (September 2009). Accreditation allows for informed decision-making when selecting a laboratory by demonstrating competence, impartiality and capability. Although numerous accreditation programs exist for a variety of areas from food and agricultural testing services to environmental analysis, I am not aware of any specific to dietary supplement testing.
There are a few programs out there that allow laboratories to demonstrate they know what they are doing. For example, NIST (National Institute of Standards and Technology) has created a laboratory quality assurance program designed for dietary supplements. Participation in such a program is especially valuable because it not only demonstrates competence in performing a particular assay, but it also makes evident efforts to improve overall laboratory performance. Catherine Rimmer, Melissa Phillips and Laura Wood from NIST have graciously agreed to introduce the NIST programs that focus on improving the comparability of laboratory measurements for dietary supplements.
NIST, Helping You Know What’s in the ‘Laboratory Box’
In 2007, NIST and the Office of Dietary Supplements (ODS) at NIH started a Dietary Supplement Laboratory Quality Assurance Program (DSQAP). To address the diversity of the dietary supplements, which encompasses a huge range of analytes and sample matrices, the DSQAP has been broken into a series of smaller programs: fat-soluble vitamins, water-soluble vitamins, botanicals, fatty acids, nutritional elements and contaminants.
For the first few exercises, participating laboratories were provided a control sample with target values and an unknown sample with no assigned values. The program has subsequently evolved to include multiple samples with varying matrices. For example, where once laboratories would have received an infant formula control and infant formula sample for the measurement of niacinamide, they may now receive infant formula, breakfast cereal, multivitamin tablets and gummy vitamins to challenge a range of analytical capabilities. Laboratories have expressed an interest in more “survey” type exercises, as documentation that performance is within the consensus range can be used to illustrate competency to inspectors.
How Does the DSQAP Work?
First, the program is free and open to all interested laboratories. Twice a year, electronic participation forms are distributed along with a list of study analytes and matrices. Laboratories enroll in the studies that are applicable or interesting to them. NIST compiles the list of participants, then packages and ships the requested samples. The due date for reporting of results is usually three months from the initial shipment date. Reports with information about how your laboratory performed relative to the rest of the community are returned two to three months after NIST receives the majority of the data.
There is considerable latitude in the program. Since its purpose is to give you the opportunity to demonstrate that your in-house analytical method is appropriate to the analysis and that performance is satisfactory, NIST does not prescribe methods for the program. You are free to use your method of choice. Questions about an exercise are welcomed, and NIST will send additional information, such as recommended sample sizes, extraction conditions or chromatographic and detection parameters.
Is This a Proficiency Testing Program?
Technically, the DSQAP is not a proficiency testing (PT) program, as NIST does not provide pass/fail results. Instead, the DSQAP is an inter-laboratory comparison program whose goal is to help laboratories make better measurements. Without the technical requirements of a PT program, NIST is free to contact participants to say, “Your results appear to be off by a factor of 10. Would you like to check your calculations and resubmit your results?” And if you miss a reporting deadline, you can still email that data when available.
Although your results will not appear in the final report, your data will be entered and an individual updated graph showing your results relative to the other participants will be provided to you.
What Are the Benefits to My Laboratory?
In the data report, you are provided with the information necessary to determine your own laboratory proficiency. The DSQAP is an anonymous program, so participating laboratories receive unique identification codes with each exercise and NIST will not release the data associated with your name without your permission. You may provide your reports to regulatory agencies and customers as evidence of participation in a QA program and as a demonstration of method performance.
What Should I Do If I Think My Results Are Wrong?
Send an e-mail to let NIST know about your problems so that it can help you solve them. To NIST, “bad” results are better than no results as they give them a more realistic picture of the areas where the community needs help. This type of knowledge helps NIST plan educational activities and future Standard Reference Materials.
Editor’s Note: To get your laboratory involved in the DSQAP send an email to DSQAP@nist.gov; you will be added to the mailing list for notification of upcoming exercises and events. For more information or to see reports from past exercises, visit the website at http://www.nist.gov/mml/analytical/dsqaprogram.cfm.
