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Good Manufacturing Practices: What They Are, and Why They're Important
I. Background Good Manufacturing Practices (GMPs) are regulations that describe the methods, equipment, facilities, and controls required for producing human and veterinary products, medical devices, and processed foods. The U.S. regulations are outlined in the Code of Federal Regulations (CFR), are enforced by the Food and Drug Administration, and are called "current" Good Manufacturing Processes to emphasize that the expectations are dynamic. GMPs define a quality system that manufacturers use as they build quality into their products. GMPs help ensure that products are safe, properly identified, and of the correct strength, pure, and of high quality. Drugs Again, GMPs are required of companies that manufacture human products, including drugs. Drug products include both prescription and over-the-counter drugs. Examples of products considered by FDA to be over-the-counter drugs include instant hand sanitizers, skin protectants, antibacterial soaps, and sunscreens. Because they make a specific claim ("sanitizing", "protection", etc), theyre considered drugs. Though these products are over-the-counter, and not prescription drugs, FDA mandates that GMP compliance must be maintained with the same level of care. Cosmetics GMPs are also required of companies that manufacture cosmetics. While traditional make-ups are examples of cosmetics, so are shampoos, lotions, creams, perineal washes, and other similar topical products. Medical Devices Regarding medical devices, FDA considers any disinfectant specifically marketed for use on medical devices to be medical devices themselves. Thus, if a disinfectant has label text stating it can be used on wheelchairs, hospital beds, IV poles, walkers, hydrotherapy bathing units, patient lifts, or any other medical devices, FDA considers that disinfectant to be a medical device. The FDA therefore requires that the disinfectant be manufactured under GMPs. II. Touring a Manufacturing Facility If you're considering doing business with a supplier registered with the FDA, you should seriously consider taking a tour of their manufacturing facility. Businesses that manufacture cosmetics (shampoos, perineal wash, lotions, creams, etc.) or over-the-counter drugs (instant hand sanitizers, protectant creams antibacterial soaps, etc.), should be adhering to GMPs. A company's GMPs are usually outlined in the form of Standard Operating Procedures (SOPs). SOPs are written guidelines that describe in detail how products are manufactured, from the initial formulating through the filling process. Keep in mind, however, that just because a company has SOPs, it doesnt necessarily mean that they are following them. This is why the FDA conducts inspections of facilities, and also why they require companies to do internal inspections (called "self-audits"). FDA also requires that manufacturers audit their suppliers, so that the quality of incoming materials is assured. While end-users are certainly not required to audit their suppliers, it's wise to do so whenever possible. When walking through a FDA registered facility, it's reasonable to assume that they are supposed to be following GMPs, and should have SOPs in place to ensure that theyre doing so. Even so, some manufacturers are unaware of their regulatory responsibilities. So its always best to start with basic questions such as the following: 1. Are you registered with the FDA? 2. If so, in what capacity? (Cosmetic Manufacturer, Medical Device Manufacturer, Drug Manufacturer) 3. Do you follow current Good Manufacturing Practices? 4. Do you have written Standard Operating Procedures in place? Note that in an actual audit or inspection, the manufacturer is expected to provide actual documentation of their responses, such as a registration form, SOP manual, etc. During your tour of the production facility, you will likely be shown different areas such as an incoming materials room, blending area, fill lines, laboratory, etc. Although there are different types of questions pertinent to different areas, the primary points are two-fold: 1) Do the SOPs work towards ensuring quality?, and 2) Are the SOPs being followed? All questions should be asked with these two points in mind. Here's a breakdown of basic areas of production, with a few pertinent questions and things to look for. Incoming Materials Room All incoming materials should be quarantined until an identity check is performed. There should be a way of identifying the status every piece of incoming material, such as a "Quarantined" or "Released" sticker or label. Identity checks vary, with some merely being visual verification that the product received is exactly what was ordered. Some companies, however, will not assume that the material label is correct, and will require a Certificate of Analysis from the supplier and even do a laboratory check of the material before it is released. Some questions to ask: 1. How do you know the status of incoming materials? (If they state they use status labels, look and see if items are, in fact, labeled) 2. How do you verify the incoming product is actually the product ordered? 3. Do you do any type of laboratory check? 4. Do you require a Certificate of Analysis from your supplier? Blending / Manufacturing Process The actual creation of the product, also called the "blending" or "manufacturing" process, must be tightly controlled to ensure product integrity. Batch sheets are commonly used to document the process, though sometimes they can be called by different names such as "Production Records", or "Process Control Sheets". Batch sheets should include the product formula, and the specific steps used to create the product. Batch sheets may also include the filling process, as this is part of the production process. Some questions to ask: 1. How do you know if a blending tank is clean? 2. Do you have documentation of when it was last cleaned? 3. Do you use any type of batch or production record to document the blending process? 4. How do you document what raw materials are used in the batch? 5. Do you record the lot numbers of each raw material used for later reference? (In case of problems with that batch.) 6. How do you confirm or verify the person adding the ingredients is doing so accurately and correctly? Do you have any witnesses that sign off on each step? 7. Are specific ingredients measured or weighed before being added to the formula? 8. Do you have weigh scales calibrated to ensure accuracy? How often? Do you record each calibration? 9. Do you record mixing times to ensure compliance with blending directions? 10. Are there any quality control checks before the product is released for filling? 11. Are there any microbial checks before the product is released for filling? Filling Process The filling process must be carefully monitored, as it is a potential source of microbial contamination. Equipment must be cleaned, including transfer hoses, pumps, and fill heads. Proper cleaning should include more than just a water rinse. It should involve actual sanitization of the equipment. This process should be detailed in the SOPs, and documentation that it was done should be available (otherwise, how do you know the equipment was cleaned prior to use?). The FDA does not require a specific cleaning method. They do require, however, that whatever method used actually works, and that validation of its effectiveness is available. Some question to ask: 1. How do you know the equipment was clean before it was used to fill your product? 2. Do you have documentation that it was cleaned? Is it signed & dated by someone? 3. Do you have a cleaning SOP? 4. Does this SOP include sanitization? 5. Does the process include transfer hoses, pumps, and fill heads? 6. How do you know your cleaning/sanitization process is effective? 7. Do you have validation (or proof) that the cleaning process is effective? 8. Do you document how much product was filled out of the tank? 9. Do you have lot numbers that go on each container? If not, how do you track what containers go where? 10. Do you conduct microbial checks on finished product before releasing them for shipment? Water System Water is frequently used in cosmetic products, and the water used must be acceptable. Many companies prefer not to use city water, as the quality of that water can vary. Instead, some companies use deionized or even purified water. If you tour a facility that uses deionized or purified water, consider asking the following types of questions: 1. Would you describe your water system for me? 2. How do you check the quality of your water? 3. How often do you check the water system? Quality Assurance Laboratory FDA requires that cosmetic and drug products are free of microbial contaminants. Manufacturers should conduct microbial checks of their products before it is released for shipment. Some questions to ask: 1. Do you conduct microbial checks of your product before release? 2. If not, how do you know your products do not contain microbial contamination? 3. If so, when do you conduct the checks? (After blending? After filling?) Other Considerations There are other areas to consider when touring a GMP facility. For example, a Complaint System should be in place in order to look for potentially undesirable trends associated with the product. This system documents every complaint that is received, and should include the specific problem reported, how that problem was investigated, and how it was eventually resolved. Even if no complaints have been received, a SOP should be in place detailing how a complaint will be handled. Additionally, employee training should be an on-going process at GMP facilities. Training topics can vary, but documentation of the topic, the date, and all those attending is necessary. Some questions to ask: 1. Does your company have a SOP detailing how complaints regarding FDA products are handled? 2. Do you have an individual or group responsible for handling complaints? 3. How are complaints tracked? 4. Does your company have on-going training? 5. Is this training documented? 6. What type of training topics have you had over the past year? Conclusion Because the FDA is responsible for monitoring the production of food and drugs, they help protect the American public against unsafe products. Accordingly, they take their role as investigators seriously, and often find non-compliance issues at facilities they tour. When this occurs, a "483" is issued to the company, which details out the specific concern(s) of that investigator. Its not uncommon for a company to receive a "483", sometimes with several items on it. When the non-compliance is of a more serious nature, or the list of concerns is lengthy, there may be more cause for concern. However, if the items listed are critical, or the company has serious, chronic defects in their GMP compliance efforts, the FDA can also issue a "Warning Letter". While a "483" should be responded to and dealt with promptly, a "Warning Letter" is very serious, and must be handled with due haste. As asking a company if they've received a FDA Warning Letter can be uncomfortable, copies of inspection reports (and associate 483s or Warning Letters) can be obtained through the Freedom of Information Act. Ensuring a potential supplier is compliant with current Good Manufacturing Practices is important, as it helps ensure both product and corporate integrity. While personal tours are not always possible, it is reasonable to at least ask these questions through other avenues of communication such as telephone or mail. Openness regarding this issue is a critical step in forming relationships with suppliers, and ultimately benefits the residents and patients.
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