By Eric Brand

U.S. FDA law currently regards granules as dietary supplements. In the USA, specific laws regarding cGMPs (current Good Manufacturing Practices) apply to dietary supplements, and many practitioners are uncertain about the degree to which these laws affect their compounding practices. While there are fundamentally some gray areas in the law, it is good to for practitioners to be aware of the general scope of these new laws and their impact on herbal pharmacies.

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The FDA’s cGMP laws primarily revolve around maintaining good records and clean, safe manufacturing practices. While the laws are primarily focused on manufacturers, individual compounding facilities technically do not have an absolute exemption from cGMPs. In general, the FDA has stated that they will exercise “discretionary enforcement” for licensed practitioners that see patients on a one-on-one basis. In other words, minimal enforcement is expected as long as a trained professional sees a patient individually and prepares medicine that is customized for their case. Enforcement discretion does not apply to clinics that prepare medicine in large batches and dispense products to customers that have not had any individual evaluation.

In terms of dietary supplements and GMP law, different regulatory tiers apply to companies that simply “hold” sealed bottles rather than companies that “manufacture” products. The responsibilities of companies that hold products (such as a retailer that stocks sealed bottles on the shelves) are much less complicated than the responsibilities that apply to manufacturing. In other words, selling sealed bottles

Technically, any time the sealed bottles are broken and individual ingredients are compounded together the FDA regulates the company as a “manufacturer.” This creates a gray area because most individual practitioners and clinics do open bottles and compound products together, but they tend to see patients on a one-on-one basis and thus fall under discretionary enforcement. The rub is that despite the FDA’s official statement that discretionary enforcement applies to individual practitioners, technically the scope of the law clearly regards compounding of custom formulas as “manufacturing” (thus subject to cGMP rules).

Achieving true cGMP-level compliance is unrealistic for most small businesses and compounding pharmacies. Compliance requires the management of a host of complex details and requires a facility that contains an appropriate configuration of sinks, surfaces, entrances, temperature control, etc. The cost of setting up and maintaining such a facility generally runs into tens if not hundreds of thousands of dollars, so very few Chinese medical dispensaries are able to reach cGMP compliance. Such pharmacies tend to rely on the provision for “discretionary enforcement,” and in most circumstances the risk of problems is quite low if the clinic is well-managed. Unfortunately, there is a fear that enforcement discretion could go out the window if a true adverse event and associated lawsuits arose, so many clinics choose to be as vigilant as possible when it comes to safe compounding practices and well-organized recordkeeping.

Setting Up

When it comes to setting up a granule pharmacy, the first step is to start with a reliable supplier. There are multiple quality granule producers to choose from, and choosing a good source will save significant effort later. As mentioned above, assessing the quality of the product itself is essential. Beyond choosing the right product in terms of quality, consistency, and value, it is also important to assess your supplier on the basis of GMP issues.

A supplier that runs a tight ship with their own GMP management is well-positioned to offer support when it comes to helping your clinic maintain good records. While there is general consensus that true GMP compliance is beyond the reach of the average clinic, maintaining a good paper trail and being informed and proactive about safety issues will ultimately be very beneficial in the unlikely event that FDA issues ever arise. Below are some of the basic things to keep in mind:

Choosing a Supplier

As required by law, GMP-certified manufacturers have safeguards in place to track their inventory, manage recalls, record adverse events, etc. All the key factories that produce granules have GMP-certification in their home country, yet some factories have far more wide-reaching efforts than others when it comes to meeting international regulations. For example, some factories have only local GMP certification while others also have Australian TGA certification or third-party certificated U.S. FDA cGMP certification.

There is also significant variation in the complexity and number of tests that individual manufacturers employ. For example, some companies test for only three pesticides while others test for 150 or more. Some labs use equipment that tests ppm (parts per million) while others test with equipment that can register ppb (parts per billion), so even the specified detection limit for the tests can vary. Some companies use only in-house testing while others combine in-house testing with independent third-party testing.

Testing for things like pesticides, constituents, and heavy metals can be quite expensive, and the house standards can vary significantly. For example, companies often set internal standards for heavy metals based on the national standards that correspond to their target market, and the allowance for various heavy metals varies between countries such as China, Japan, and Germany. This means that different companies may have different acceptable limits when it comes to testing results, and sometimes even the same company has requirements that vary depending on what market they are servicing with a particular product.

When choosing a supplier, it is also good to assess the degree of transparency that they provide. Do they use ethanol in their extractions or water only? Do they capture and re-introduce essential oils? Are the excipients (starch, dextrin, etc.) and concentration ratios disclosed on the label? Are certificates of analysis or testing results available upon request? Can the company track the lot numbers of your orders or is this something that needs to be done manually by the clinic? Most importantly, is the company accessible and forthcoming with information or is it difficult to find the answers that you need?

Documenting Procedures

Beyond having adequate facilities and training, true GMP compliance is characterized by extensive records that document Standard Operating Procedures (SOPs) for virtually every task that is undertaken. Despite the fact that small pharmacies do not have the resources for true GMP compliance, it is possible for a pharmacy to maintain effective SOPs that document the tasks and procedures that fit their needs. If documentation is present that specifies procedures and their implementation, the clinic will appear rigorous and vigilant to an inspector in the unlikely event that the clinic is audited by the FDA (this would typically be unexpected for small clinics unless adverse events or poor business practices are reported). While no one truly knows to what degree good SOPs will protect a small business that cannot be truly GMP compliant, the general consensus is that strong SOPs will leave a favorable impression and help to minimize problems.

When designing SOPs, one should try to cover all the minute details. What is the task, who performs it, when do they perform it, what action should be taken if a problem arises? SOPs should be made for all the different tasks that the clinic performs. Someone should sign off when they receive the shipment and they should log the lot number. It doesn’t matter whether the system is high-tech or just handwritten on paper, but there should be a paper trail that allows each batch of herbs to be tracked to the patients that received them. The lot numbers should be recorded when the shipment comes in, and a system should be developed to follow who received herbs from that particular lot. If something goes wrong (product recall, broken glass jar in the clinic, etc.), a procedure should be documented to fix it. The successful resolution of the problem should be documented as well.

SOPs should also be established for things like routine maintenance and cleaning. Who sweeps the floors and how often do they do it? What steps are taken to minimize pests such as insects or rodents? Are employees required to wear clean uniforms, gloves, etc? All these details should ideally be documented, even if the details seem like common sense. For example, employees should generally be prohibited from eating in the compounding space and the herbs should not be stored on the floor. Most clinics do have such rules but often there may be no documentation that these rules exist and are followed. Vigilance when it comes to establishing compounding procedures means identifying these issues, writing SOPs, and maintaining logs that show that the SOPs are being used.

Equipment

Generally speaking, a good workspace is required. Most practitioners use a large container to mix the granules together, and this container should be cleaned in between prescriptions. A scale that is accurate to 1/10 of a gram should be used, and an SOP should be created to periodically calibrate the scale to verify its accuracy. True GMP facilities often take the extra step of having a method to check and log that the correct herbs were selected and the correct amount was weighed, but many small private clinics do not go this far.

Beyond the shelves, the workspace, and the scale, little equipment is required for a granule pharmacy. A good method of mixing the ingredients together in formulas is necessary, and there should be enough space in the mixing container to ensure that the formula is mixed adequately.

Designing Labels

According to FDA law, all products should be labeled. The FDA website itself (www.fda.gov) offers the most comprehensive guidelines for U.S. labeling laws, and similar guidelines exist for the labeling requirements in other countries. Labeling requirements are detailed and are beyond the scope of this book, but a few general guidelines are noted below.

In the USA, granules are classified as dietary supplements. Technically, their labels require a “principle display panel” that contains the identity of the product; this label is the center panel that faces the consumer. English is the preferred language when it comes to name of the product and its ingredients, and the ingredient list should be included in the panel to the right of the principal display panel. A box titled Supplement Facts must be located to the right of the principal display panel, and the FDA publishes very precise guidelines regarding font size, bold text, the lines within the box, etc. Any other (inert) ingredients must also be listed and precise dosage directions should be included.

A few other general pieces of information are also required for proper labeling, including the name and address of the supplier, the country of origin, the net weight, and other details. A lot number or prescription number must be included on the label, which should be linked to a paper trail that can be used to identify the batch of materials that was involved in production. Many detailed resources exist for researching this information, but the “take-home message” is that including a label on the products that are being dispensed is generally something that advocates of safe compounding guidelines universally endorse.

Many practitioners do not currently label the products they dispense and sophisticated tracking systems are rare. In truth, for most practitioners there is probably little reason to worry about issues such as cGMPs because problems are unlikely to arise. The discretionary enforcement status quo minimizes the risk for small compounding pharmacies and the main impact of cGMP laws will be felt by large suppliers rather than individual practitioners. Nonetheless, the world of herbal medicine is becoming subject to constantly increasing scrutiny and regulation, and practices that have significant assets and/or high risk circumstances may benefit by implementing more rigorous quality control and tracking systems.