Since the passage of DSHEA (Dietary Supplements Health And Education Act) in 1994, the dietary supplements industry experienced a dramatic growth trend which tapered off toward the end of 1999¹. Today, functional foods such as sports beverages are experiencing increased popularity and explosive market growth². Many feel that the economic downturn in the U.S. was a key factor in the slowdown of the dietary supplement industry’s growth³; however, others blame this downturn on the demise of consumer confidence which followed the appearance of a number of news stories that reflected poorly on the dietary supplement industry⁴. In short, these stories implied that the industry lacked adequate quality control procedures and generally could not support their products’ label claims⁵. Although many feel that the dietary supplement industry has been unfairly attacked, almost everyone agrees that there are some companies that have had serious quality issues. However, this industry is not alone in this regard.

Quality Control issues are not unique to the dietary supplements industry. The pharmaceutical industry continues to have quality issues to this date⁶. A cursory review of the Food and Drug Administration’s (FDA) Enforcement Reports demonstrates this point clearly⁷. Dissolution failure, sub-potency, super-potency, mis-labeling and a number of other problems continue to plague both pharmaceutical companies and nutra-ceutical companies.

We will examine a major area where quality problems occur: method transfer. A comparison between the pharmaceutical and nutraceutical industries’ approach to the issue of method transfer will be reviewed along with strategies for companies that are working through method transfer problems.

Definitions
Let’s start with the definition of method transfer as it relates to this article. “Method transfer” refers to the process of applying analytical test methods developed for raw materials to finished dosage products such as those that are sold to the consumer market. For instance, let’s take a hypothetical contract manufacturer for our example which we will call ABC Company (This example will be referred to later on in the article). ABC Company manufactures a ginkgo biloba-echinacea blend in a soft-gel form. They procure both ginkgo biloba extract and echinacea extract, which are both in powdered form. The manufacturing unit blends these two raw materials along with a vegetable oil, lecithin and a few other excipients and produces the soft-gelatin capsules. These are packaged into bottles containing 60 capsules each.

When they receive the ginkgo extract, they send it to an independent laboratory for analysis. The tests conducted are for flavonol glycosides and terpene lactones, which are the marker compounds commonly used to standardize gingko extracts. The echinacea is also analyzed by the independent laboratory for total phenolic content, which is a commonly used marker compound set for echinacea. Both products meet the supplier’s Certificate of Analysis (C of A) specifications for marker compound levels. In addition, the lab conducts identity testing on both raw materials to confirm the botanical species used. Both ingredients are authentic in our example.

The contract manufacturer releases the materials from quarantine and produces the product. The product is to be shipped to another hypothetical company we will call Uvula, Inc. Uvula distributes the product through various stores across the United States. Before it accepts the product on its dock, Uvula requires ABC Company to send the product out to an independent laboratory for analysis to confirm the label claim (we will also come back to this scenario later). For now, let’s turn our attention to a hypothetical contract pharmaceutical manufacturing company called PillCo.

PillCo is under contract to manufacture APAP (acetaminophen) USP 500mg caplets for the Ronko Pharmacy chain. PillCo produces the product in its facility and packages it into bottles containing 100 tablets each. It has an independent laboratory assay incoming acetaminophen raw material as per the USP 25 method to confirm that it meets the specifications for USP grade APAP⁸. Once the material is cleared from quarantine, PillCo encapsulates the product. Samples from the finished lot are sent to an outside lab to confirm potency (label claim). The lab uses the USP 25 method for Acetaminophen Capsules⁹.

At first, the reader will see many similarities between the contract dietary supplement manufacturer and the contract pharmaceutical manufacturer. In our example, both obtain raw materials and send them out to a contract lab that tests the raw materials. Both companies manufacture a product for another company and have to confirm potency after manufacture. However, at this point, we begin to encounter significant differences between the two companies.

The laboratory testing acetaminophen for the pharmaceutical company, PillCo, draws on established compendial methodology developed for the raw material. When it tested the finished product (in this case a capsule), it utilized compendial methodology specifically developed for that finished dosage formulation¹⁰. The raw material uses a simple spectrophotometric assay while the finished dosage product requires sophisticated HPLC equipment for analysis¹¹. In this case, the method transfer occurred some time ago with the development of a compendial method for the finished dosage form. During the method transfer, the limitations of the spectrophotometric assay procedure were realized and the utilization of an assay with greater selectivity was utilized¹².

The major advantage of working with pharmaceutical-type drugs is that one is mostly working with one (or sometimes a few) target compound(s), often referred to as the active pharmaceutical ingredient (API). When the method is transferred to finished dosage forms, the compound is often mixed with some coloring agents, binders and coatings. Usually, the matrix challenges encountered from these excipients are easily overcome by a skilled chromatographer¹³. Additionally, the drug developer often submits the analytical methods for the standard finished dosage forms as well. In the case of ABC Company’s ginkgo-echinacea product, the situation is quite different.

Natural products are some of the most complex matrices found in the analytical chemistry world¹⁴. Ginkgo and echinacea are both botanical materials obtained in nature. Because they are agricultural products, lot-to-lot variations are expected¹⁵. In his Handbook of Phytochemical Constituents of GRAS Herbs, well known botanist James Duke identified approximately 183 chemical constituents in ginkgo biloba leaf. Further, he identified more than 150 constituents for echinacea species in general¹⁶. In both cases, one of these ingredients is an essential oil. Plant volatile oils (essential oils) can contain a large number of volatile compounds such as monoterpenes, oxygenated sesquiterpenes and oxides, to name a few¹⁷. The essential oil of lavender contains more than 400 compounds alone¹⁸. Thus, where the acetaminophen capsule mostly consists of a single drug ingredient and a few minor excipients, the ginkgo-echinacea blend contains literally hundreds, if not thousands, of phtyochemicals.

The development of validated analytical methods to measure a few marker compounds in a single botanical is often very challenging. When a lab tries to take a method developed for a single botanical in the herb or extract form and transfer the method to a multi-component, finished dosage product, significant challenges are usually encountered.

Often, without extensive method development and research, it is not possible to verify the marker compound levels against the label claim (i.e. Supplement Facts Label). This is especially true when the compounds found in two or more of the botanicals are in the same class, as with the case with pygeum and saw palmetto¹⁹. In this case, both of these botanicals contain fatty acids and sterols, which makes it very difficult to determine how much of each marker compound is coming from each botanical.

Another consideration is that of the excipients. Many botanical constituents will bind to excipients to some degree, making complete extraction difficult²⁰. This is well demonstrated in the Kava Kava method developed and validated by the Institute for Nutraceutical Advancement (INA). Under the sample preparation section, it states, “Kava extract is often blended or spray dried onto various carriers. This method is not validated for these matrixes. To successfully assay powder samples, it is necessary to develop a sample preparation step that recovers the kavalactones from the carrier. This sometimes can be accomplished by first extracting with pure methanol or water. However, no general guidelines can be given due to the wide range of carriers used and their individual chemical and physical characteristics”²¹. I can confirm this from personal experience in the lab; while researching extraction techniques for kava extracts, we found that recovery from a spray dried extract could vary widely based on the solvent system used to prepare the extract. In some cases, adding water then alcohol resulted in higher recoveries, while the opposite was true in other cases²².

Compounds found in natural products are often very unstable and degrade over time. They are affected by heat, light, moisture and a variety of other conditions including the types of containers that they are shipped in²³. Once extracted from the botanical, many constituents will begin to degrade rapidly (e.g. hyperforin in St. John’s Wort)²⁴. This problem can be compounded when additional constituents from other botanicals in the blend are present. Incompatible constituents dissolved in a solvent system (such as would be done for quantitative analysis) could begin to cause each other to degrade, bind to each other, or form new compounds through reactions.

There are some new compendial methods for botanicals that have appeared in the USP 25/NF 20, such as Valerian, which offers methods for both the herb and for some finished dosage forms such as tablets²⁵. However, these are few and far between. Compare this to the number of entries for the various finished dosage forms and combinational blends of acetaminophen. In the USP 25, there are 21 monographs for acetaminophen, plus the monograph for the single ingredient raw material²⁶.

From the examples above, it is easy to see that our fictive PillCo will most likely not encounter any problems when it sends its sample to the contract lab for analysis, provided that the lab is competent. In contrast, we would expect ABC company to encounter difficulty finding a reliable laboratory that could even conduct analysis on its product. Further complications arise when one considers the nature of ABC’s product form, which is a softgel.

Softgel finished dosage forms have gained in popularity over the last several years due to a number of factors. They are easier to swallow for many consumers. Encapsulation of unpleasant tasting ingredients can be accomplished so that the consumer does not taste them, and softgel suspensions containing a variety of ingredients can be achieved readily. However, to an analytical chemist, they can often present significant analytical challenges.

During the sample preparation phase, the analyst tries to isolate target compounds from the matrix (the other ingredients in the formulation). This sample preparation technique is often accomplished by liquid-liquid extraction techniques²⁷. For those not familiar with this concept, please observe the vinegar and oil salad dressing in your refrigerator. You will notice that there are two layers. One layer is the oil and the other layer is the vinegar (aqueous, water phase). When you shake the bottle up, the layers mix, but they eventually separate. In laboratory liquid-liquid extractions, we use an aqueous phase and an immiscible organic phase (solvent that does not dissolve in water) for many extraction techniques. When the sample is introduced, we partition the compounds between the phases. When the phases settle out, we can remove the layer containing our target compounds while leaving interfering matrix compounds out²⁸. Many chemists reading this will be frustrated that we have not discussed this technique in detail, which would include multiple partitions, acid-base cleanup techniques and so on. For our example, though, this will suffice.

The problem we encounter with softgels is that they often contain high levels of lecithin. Lecithin is an emulsifier and it has the effect of allowing water and oil (or water and an immiscible solvent) to mix to some degree. Thus, the analyst often finds that the separatory funnel contains an emulsion, which defeats the entire purpose of the sample preparation technique²⁹. A great deal of effort is needed to overcome this type of problem.

Another issue is that of analyte migration into the soft-gelatin shell. Research has shown that the degree to which compounds are hydrophilic can impact their migration into the gelatin shell³⁰. Familiarity with the constituents contained within the shell is often critical in the evaluation of sample preparation methods. When attempting to transfer a method for a botanical raw material to a soft-gelatin capsule, method development and validation are absolutely necessary. (Please don’t think that I am picking on softgel finished dosage forms. They just happen to illustrate the challenges in method transfer quite well.)

PillCo will most likely also have issues with finished dosage product forms. The pharmaceutical industry has many drug formulations that exist in combination, such as cough and cold formulations. However, in the process of gaining OTC approval, analytical methods were developed to validate the stability and potency of these products. This is not often the case with dietary supplements.

Many companies that have developed dietary supplement formulations have also either developed in-house or contracted with analytical laboratories to develop and validate analytical methods for their finished dosage forms. However, in my estimation, for every company that has a validated method for its finished dosage combination product, there are many that don’t³¹. As the laboratory director of an independent analytical laboratory specializing in natural products chemistry, I spend a significant portion of my time working with clients who need to develop testing protocols for their finished products (as well as obscure ingredients)³². Perhaps the most difficult situation is when a client’s product contains a blend of 10 botanicals that are not standardized extracts. There is only one way to evaluate the label claim, which we will discuss below.

By now, you have probably begun to develop an understanding of the issues that arise when an analyst wishes to test a finished dosage form and only has methods available that were validated for raw materials. This is usually the point at which quality control in manufacturing breaks down in the dietary supplement industry. Please be assured that many companies have invested significant time and money in the development of analytical methods for their proprietary formulations so that they can verify label claim and validate shelf life. Often, the manufacturer will work with a contract laboratory that understands natural products chemistry and can develop testing protocol for routine QC (quality control) use. This is a little more challenging for our friends at ABC Company, because ABC is a contract manufacturer. Let’s see if we can gain insight into its unique situation.

There are a number of companies that promote, distribute and sell dietary supplements in the U.S.³³. Many of these companies offer several products to their target markets. How-ever, not all of them make their own products. The manufacture of finished dosage pharmaceuticals and dietary supplements is a highly evolved science that requires significant expertise as well as capital investment. Many companies have ex-perts who develop formulations for consumer health care based on their expertise in nutrition and health. It is not always feasible for these companies to make their own products, which would most likely mean allocating additional resources otherwise earmarked for R &D.

Fortunately for such entities, contract manufacturing companies exist. Contract manufacturers often specialize in specific areas such as softgel manufacturing, liquid supplements or tableting &encapsulation. They have experts who understand how to blend and formulate a product together into a form that will be suitable for consumer use. This is the good news.

The challenge that contract manufacturers face is that they often formulate numerous types of products. Each of these products is a little different, even if they contain similar ingredients. When they need to test their finished product, the contract manufacturer is often faced with a costly method development charge from a third party lab. This in turn must be passed on to the client, who may not wish to pay for such R &D. In the past, many contract manufacturers of dietary supplements relied solely on their production records to demonstrate that a particular production run was properly prepared. They would demonstrate through records kept on file that they used the correct ingredients in the correct amounts. This, combined with analytical testing on the incoming raw materials, usually sufficed to meet the needs of their clients. This is changing now.

Many companies want to see analytical reports from third party labs that prove that their products are meeting label claims before they accept shipment from the contract manufacturer. In many cases, no methods exist which are capable of meeting these analytical needs. This can be a difficult and precarious situation for the contract manufacturer and the client if the product ends up in a consumer survey as having failed label potency claims. Even if the consumer survey is flawed, regaining consumer confidence can be difficult. However, there may be steps that can be taken to prevent these problems from arising.

In most cases involving methodology transfer issues, there are three or more parties involved: the contract manufacturer, their client, and the third party contract laboratory called upon to conduct label claim analysis. Here are some problems that I frequently encounter when called upon to assist in method development after the fact. By ‘after the fact,’ I mean: ‘once the product has been formulated and manufactured (or often distributed and consumed as well).’

1. No retained samples of the raw materials used in manufacturing of the product. This happens more than you might imagine. It is often difficult for high volume contract manufacturers to retain samples of every ingredient used for every client’s product. In some cases, they would need a warehouse just for retains. However, this is one of the most valuable steps that can be taken to assist in method development and problem solving. By supplying the lab with each ingredient used in manufacture, the lab can create controlled mock-ups of the formulation and compare them to the finished dosage product. In addition, the lab can test each single ingredient to see how it compares to the original supplier’s C of A. The ability to supply retained samples of raw materials is especially important when the label claim is based on the weight of the powdered herb and not on the level of a marker compound. In order to verify a claim, based on the weight of the botanical alone, the analyst must test a marker level in the raw material and compare it to the level of the marker in the finished product. From this data, he can extrapolate the percent of label claim.

2. Proprietary blend of ingredients purchased pre-formulated from another supplier. This issue is most often encountered with Traditional Chinese Medicine formulations (TCM). Often, the herbal ingredients arrive from China pre-mixed and are added to a product with or without further blending. It is nearly impossible to determine the amount of each ingredient in the blend without entering into a full-scale research project. Projects of this type can cost upwards of $50,000 or more for the first sample if the customer needs accurate quantities of each botanical measured. The solution for the contract manufacturer is to either: a) have the materials sent to its facility unblended and mix them on-site so that one can pull retains of each herb in the formula or b) have the supplier of the blend send retains of each single herb used in the formulation. I have had the unique opportunity to travel to China and work with manufacturing facilities on such projects and I can tell you that it is often difficult for the company to supply such single ingredients. Many times, the herbs arrive and are ground together or extracted together as a formula. The need for these single retains did not exist in the past and many companies in China are not fully up to speed with the new and rapidly changing U. S. market demands. In addition, many domestic labs in the U.S. lack the expertise to analyze Chinese botanicals, save for ginkgo and ginseng.

3. Formulations prepared by contract manufacturer without adequate stability studies. Often, the pace of manufacturing is swift in the dietary supplements industry compared to standard OTC products in the pharmaceutical industry. What is hot today is not tomorrow; the supplement’s life cycle may be short lived. This is not to say that dietary supplements don’t have market longevity. Take echinacea, ginkgo, saw palmetto and ginseng, for instance. They continue to experience strong market shares today. The benefits of saw palmetto in the treatment of BPH (benign prostratic hypertrophy) is so well documented that the U.S. Pharmacopoeia considered moving the monograph for saw palmetto from the National Formulary (NF) grade to USP grade³⁴. However, for those products that might be made only a few times a year for select clients, it can be cost prohibitive to conduct these studies. Unfortunately, without them, there is no way to tell if the formulation is degrading over time due to compound interactions. Contract manufacturers might wish to discuss this issue with their clients before commencing with manufacturing. If they find that they are frequently producing similar formulations, it may be beneficial to conduct stability studies on a base formulation. However, one must keep in mind that, just because one version of a formula is stable, it does not mean that all permutations of that formula will also be stable.

4. Initial Quality Control testing of incoming raw materials never conducted. Impossible, you say? Not really. This happens frequently even though it occurs less often than in the past. When a contract manufacturer establishes a relationship with a supplier of a raw material, the contractor may purchase many lots over time. The vendor may provide a C of A with each product lot. The contract manufacturer may do skip-lot testing as well. However, according to Murphy’s Law, the batch you fail to test will be the batch that fails testing. As an analytical chemist, I have encountered this problem numerous times in the industry: Goldenseal that turns out to be berberis radix; Echinacea purpurea that is actually a blend of echinacea species; SAMe that contains no SAMe! It happens. And it happens to many people who are basically honest folk. How to avoid this problem? Batch lot testing. There are many labs that offer substantial discounts for companies that wish to contract for ongoing testing. The NNFA GMP program mandates that all botanical raw materials be batch lot tested for identity every time³⁵. They require this as well as a number of other protocols because of the known lot-to-lot variations that occur in agricultural products. To put this in perspective, consider tangerines. Sometimes they peel very easily and sometimes they are tough. One may be juicy and sweet while another is mealy and sour. Nature does not offer the same reproducibility that synthetic organic chemists can (well, in the case of natural products profiles, at least). I investigated label claim issues for several companies that distributed goldenseal formulations. Their in-house lab was not able to obtain results that compared to the label claim for goldenseal alkaloids. Upon investigation in our laboratory, we found that the product was not goldenseal, but in fact was berberis, a lower cost substitute. Although both botanicals contained berberine, a major quaternary alkaloid, only goldenseal contains hydrastine. Thus consumers were not getting what they paid for. The investigation showed that most of these companies were supplied from the same source which relied solely on their vendors’ C of A. Ouch!

5. Dishonest Business Practices. Unfortunately, this is something we all have to be cautious of. Many companies work very hard to continually improve their quality and the industry’s quality in general. Unfortunately, there are still near-sighted opportunists who are only interested in the bottom line. The pharmaceutical industry faces this same dilemma. Numerous companies each year have products recalled due to a lack of GMP protocols in their facility³⁶. Although the FDA has yet to finalize the dietary supplement industry GMPs which were mandated in the 1994 DSHEA act, pharmaceutical GMPs have been in place for some time. In fact, many dietary supplement manufacturers are modeling their companies’ internal GMPs on the pharmaceutical model in hopes that they will be ready to meet the industry mandated GMPs when they are finalized.

6. Borrowed Science. This industry problem has been discussed by many experts and goes back several years³⁷. For instance, a paper is published demonstrating a method for the quantitation of certain marker compounds in a proprietary blend of extracts. While this information is valuable, one can’t necessarily conclude that the method is valid for another manufacturers proprietary blend even if they contain the same ingredients. This is because different companies prepare extracts in different ways. The ingredients that were utilized in the original paper might have been extracted in a mixture of 80:20 ethanol:water. The sample on the chemist’s bench may be an extract obtained from acetone. This was the case when I worked on TLC protocols for the authentication of St. John’s Wort extract. In this particular case, the acetone selectively extracted the dianthrones but left behind many of the flavonoids and other compounds soluble in water. When the TLC results were compared to the reference material and the handbook, they did not match. It was only after concentrating the extract 100 times that the trace amounts of flavonoids appeared in the test sample TLC plate. Fortunately, we had experience in this product and the chemistry of the compounds found in SJW herb. Otherwise, this authentic material would have been rejected as adulterated. Therefore, even though you may have XYZ’s in-house method for ginkgo-echinacea blend, don’t assume that the method will be valid on ABC’s formulation. Borrowing science must be done with a sound understanding of its pitfalls.

As the boundary between the pharmaceutical industry and the dietary supplement industry continues to change, contract manufacturers of both industries will begin to see more and more overlap in the products that they produce. In addition to the issues discussed above, there are some other key points to examine when considering method transfer to a finished dosage product.

Consider establishing a relationship with an independent laboratory that has experience in analytical method development and validation for natural products. This area is so specialized that only a handful of laboratories are able to offer this service. However, they are out there. A manufacturer might set up a consultation with a lab and discuss its product lines. One should be prepared to provide details such as the scope of the manufacturing operation, the frequency of repeat runs, the major sellers, and past problems encountered in quality control. A good laboratory will be happy to help review this material and offer some direction.

These labs have extensive experience in problem solving and can be a great resource to both the contract manufacturer and its client. In addition, contract labs offer independent verification of the product’s quality. This has become increasingly important in this industry, as well as in the pharmaceutical industry. Many contract manufacturers have good in-house labs and expertise in this area. However, they are often overworked and hard pressed to keep up with the routine workload. Outsourcing these special projects keeps the lab free to meet the day-to-day needs of your facility.

The contract manufacturer should provide educational materials to its clients so that they will understand the issues facing the operation. This is true for both nutraceutical and pharmaceutical contract manufacturers. Let’s say a manufacturer has made an OTC cough syrup in the same cherry base for 12 years. A new client requests a pineapple flavored base. Can one simply change bases? Not really. Besides the issues the provider faces with the OTC monograph, one can’t be sure that the new flavor base will be stable. What if it degrades the API? What if it is not properly preserved because a compound in the flavor base deactivates the preservative system? By educating the client up front, a manufacturer can save a great deal of trouble later. Quality is easier to build in from the beginning than to add in at the end. If the customer is geared for the cost of this quality, it can be factored into the margin as well.

We have examined some of the challenges that both pharmaceutical and dietary supplement contract manufacturers face when attempting to provide quality control testing on finished dosage forms. We have also compared and contrasted the problems that each industry faces and have offered some guidelines and suggestions to assist the manufacturer in meeting their quality needs. I hope this helped provide an understanding of the challenges faced in method transfer, as well as the problems that contract manufactures encounter when producing multi-component or unique formulations.

References

1. Geslewitz, Gina, Supplement Industry Executive September/
October, (2001)Back

2. Schofield, Lisa, Supplement Industry Executive September/
October, (2001)Back

3. Personal discussion with industry members (2001)Back

4. See consumerlab.com and consumerreports.org as well as Los
Angeles Times 1997 for examples.Back

5. See consumerlab.com and consumerreports.org as well as Los
Angeles Times 1997 for examples.Back

6. See FDA Enforcement Report for January 30, 2002 under
Recalls and Field Corrections: Drugs—Class II for examples.Back

7. Ibid.Back

8. Council of Experts, U.S. Pharmacopeia 25/NF 20, (USP
Convention Inc, Maryland, 2002), p. 16.Back

9. Ibid, p. 17Back

10. Ibid.Back

11. Ibid.Back

12. Ibid.Back

13. Bidlingmeyer, Brian A., Practical HPLC Methodology and
Applications, (John Wiley &Sons, Inc., New York, 1992),
pp 105-130.Back

14. Compare the variety of compound classes listed in the chemical profile of any botanical to that of kerosene, plastics,
blood or urine. There are literally thousands of compounds in
any plant material.Back

15. Evans, W. C., Trease and Evans Pharmacognosy, (W. B. Saunders,
London, 15th Edition, 2002), pp 61-62.Back

16. Duke, James A., Handbook of Phytochemical Constituents of
GRAS Herbs and Other Economic Plants, (CRC Press, Florida,
1992), pp 237-239, 267-269.Back

17. Williams, David G., The Chemistry of Essential Oils, (Micelle
Press, Dorset, 1996), pp 29-82.Back

18. Ibid, p 158.Back

19. Evans, W. C., Trease and Evans Pharmacognosy, (W. B. Saunders,
London, 15th Edition, 2002), p 46Back

20. Lange, et al., Kavalactone Assay by HPLC INA Method 101.007,
(Institute for Nutraceutical Advancement, Colorodo, 2002 web
published edition).Back

21. Ibid.Back

22. Personal research 1999Back

23. Evans, W. C., Trease and Evans Pharmacognosy, (W. B. Saunders,
London, 15th Edition, 2002), p 91Back

24. Lange, et al., Hyperforin in St. John’s Wort by HPLC INA Method
112.001, (Institute for Nutraceutical Advancement, Colorado,
2002 web published edition).Back

25. Council of Experts, U.S. Pharmacopeia 25/NF 20, (USP
Convention Inc, Maryland, 2002), p. 2640.Back

26. Ibid, pp 16-40.Back

27. Shugar, Gershon J. &Ballinger, Jack T., Chemical Technicians
Ready Reference Handbook, (McGraw Hill, New York, 4th ed.,
1996), pp 481-488.Back

28. Ibid.Back

29. Ibid, pp 487-488.Back

30. Personal research 2000.Back

31. Personal industry experience 1993-2002Back

32. Job Duties 1998-2002Back

33. Natural Product Industry Insider’s Buyer Guide, 2001Back

34. USP, Pharmacopeial Forum, 26(3), p 738 (2000)Back

35. NNFA GMP Program, National Nutritional Foods Association,
California.Back

36. See FDA Enforcement Report for January 30, 2002 under
Recalls and Field Corrections: Drugs—Class II for examples.Back

37. Schauss, Alexander, Supply Side Science Educational Track, (1998).Back