Last summer, we received a lot of feedback on our post entitled “What SOPs Do I Need As A Dietary Supplement Distributor?” To respond to your questions and comments about 21 CFR Part 111, we’re posting an expanded version of the original article.
If you look at the cGMP regulations for dietary supplements, you’ll notice that only 1 subpart includes the words “holding” or “distributing” in its title. With only 10 or so individual requirements, the aptly-named Subpart M, “Holding and Distributing,” is shorter than most. If you’re thinking this means there’s a much lighter regulatory burden placed on companies that simply hold or distribute dietary supplements than on companies that manufacture them, you’d be right. At the same time, you’d be incorrect to assume that regulations for holding and distributing dietary supplements are restricted to this single subpart. At least 8 of the 16 subparts that comprise 21 CFR Part 111 are applicable to holders and distributors, and all the activities outlined in these subparts require SOPs.
Subpart B, “Personnel” requires that your employees be qualified for the positions they hold and be trained in hygienic practices and warehouse operations. Naturally, this training needs to be documented. SOPs are needed to describe the procedures you have in place to comply with these staffing requirements. That’s important, because as you read on, you’ll see the warehouse staff has a lot of responsibilities.
Subpart C, “Physical Plant and Grounds” dictates that your warehouse be clean and pest-free. Dirt, insects, lubricants, or other agents could compromise the packaging or prevent labels from adhering. Your facility also needs proper drainage, adequate space, and work lighting. (Do cramped or dark conditions increase the likelihood of dangerous product mix-ups? Is any of your product sitting directly on the floor rather than on pallets?) You must also make sure that the product you hold is not exposed to more heat, cold, humidity, or light than the manufacturer recommends. (Is the heat tunnel you use for sealing shrink wrap too hot? Do you have backup refrigeration? Is there sufficient ventilation?)
Any homeowner knows that conditions in a building are not uniform; buildings have hotspots, cold spots, and damp spots. Just as the pharmaceutical industry has done, some dietary supplement holders are using a technique called “warehouse mapping” to help ensure safe product storage. In warehouse mapping, the 3-dimensional warehouse space is logically divided into many smaller blocks, a sort of Rubik’s Cube. Sensors that monitor temperature and humidity are placed in all 8 corners, the areas of the “cube” that are most subject to variations in environmental conditions. Monitoring is performed at least seasonally, as temperature and moisture will fluctuate throughout the year in most locations. Sensor data can help warehouse staff pinpoint specific areas of the facility that have inadequate ventilation or excess heat or moisture. Additional fans, air conditioners, or dehumidifiers can then be deployed to remediate any adverse environmental conditions.
Subpart D, “Equipment and Utensils” discusses the care and feeding of all machines used to control environmental conditions, and to move, store, repack, or otherwise handle product. SOPs describe proper cleaning procedures, permissible cleaning agents, and cleaning frequency. (Could this cleaning solution cause labeling ink to fade?) They describe inspection and maintenance requirements. (According to the manufacturer, how often should this thermostat be calibrated? How often is electronic inventory control data backed up?) They outline installation and operational qualification procedures. (Has your industrial scale been installed on a flat surface? Is your packing peanut dispenser blowing so forcefully that it could damage labeling or product container-closure systems?) Finally, SOPs describe all of the associated records that must be kept and the internal QA procedures to ensure it’s all being done.
Because you cannot ensure the quality of the product you distribute without verifying the quality of the product you receive, holders and distributors must implement some of the measures identified in Subparts E and F which cover Process and Quality Controls. The contents of incoming shipments must be confirmed against invoices and other paperwork, and applicable certificates of analysis must be verified. Product should be visually inspected. (Has any product reached or neared its expiry date? Is any product damaged?) SOPs which describe these activities, as well as the procedures for handling damaged/expired product must be documented and followed.
Since Subparts G through L apply only to manufacturers, packagers, and labelers, alphabetically we’re now up to Subpart M, “Holding and Distributing.” Not surprisingly, this section requires that product be held in a manner that prevents its contamination and deterioration, and preserves its purity, strength, and composition. As we’ve seen, Subparts B through F outline many of the detailed regulations you need to follow in order to protect your products…but not all of them. Temperature, ventilation, and moisture content are not just warehouse attributes; they apply to shipping environments, as well. To ensure that product receives the same protection in transit as it received in the warehouse, distributors must conduct shipping tests at various times of year and over a variety of shipping routes. (Will our product survive the stretch of Interstate 10 between Phoenix and Tucson in the middle of August?) Lastly, Subpart M requires that samples of each batch of product be retained for a specified period of time. Holders and distributors should document and follow procedures for periodically reviewing the condition of the samples and for investigating the cause of any deviations discovered. (Are the product labels legible? Is the packaging holding up? What should you do if the the appearance of the product has changed during its shelf life?)
Even after your product has been delivered, your regulatory obligations have not been fully discharged. Subpart N, “Returned Dietary Supplements” outlines quarantine and disposal requirements you must follow and quality control responsibilities you must carry out when product is returned to you. (Under what circumstances can we redistribute product? What if the return is simply the result of excess retailer inventory?)
Subpart O, “Product Complaints” outlines your responsibilities surrounding any product complaints you may receive. Remember those samples you’ve been storing according to Subpart M? Get them out, because that’s where your investigation will begin. Some of the activities here resemble those of a traditional CAPA program: determine the root cause of the problem and take corrective and preventive action. (What if the problem is not mine – what is the protocol for dealing with manufacturing, packaging, or labeling issues? What are my obligations if we receive an email from someone who claims that the product has made him sick?)
Finally, as a distributor, you would likely play a key role in any product recall.
Subpart P, “Record and Record Keeping” enumerates the data you must keep in order to respond appropriately to a recall order (as well as demonstrate Part 111 compliance in general). Conducting periodic mock recalls to test your recall SOPs will help ensure that inventory and distribution records provide the information necessary to successfully recall all targeted product.
Perhaps to those involved in pharmaceutical manufacturing or clinical research, the regulatory burden placed on holders and distributors of dietary supplements may seem light. In fairness, comparatively, it is light. But that doesn’t mean complying with all the necessary Part 111 provisions is easy or straight forward. It takes even the veterans time, effort, and expertise to develop the procedures necessary to achieve compliance, and it takes vigilance to follow and maintain them.
If you’d like some assistance navigating your way through 21 CFR Part 111 compliance, please visit us at www.polarisconsultants.com.
by Laurie Meehan
with Special Thanks to Rosanne Sylvia-Heeter, Director of GMP Compliance
