by Vince Paternoster
Even with years of awareness concerning the requirements established by the Part 111 cGMP (current good manufacturing practice) rule for dietary supplement products, companies are being cited for serious regulatory compliance deficiencies as FDA conducts inspections of the more than 1,000 dietary supplement companies in the United States. While FDA may be lenient for first-time offenders with minor problems, more warning letters are being issued. Of major concern is the worst-case scenario of not being in compliance with the cGMP rule can cause the products to be deemed adulterated by FDA.
A company is subject to the dietary supplement cGMP rule when it manufactures, packages, labels, holds or distributes a dietary supplement product. Companies with manufacturing operations tend to be more complaint with the cGMP rule; however, a large number of dietary supplement companies, referred to as own-label distributors can be less knowledgeable of their direct regulatory compliance requirements and their obligations regarding their contract manufacturers' operations. Own-label distributors are companies that have their products contract manufactured. Additionally, a company that holds and distributes any dietary supplement product needs to comply with the parts of the regulations concerning their operations and confirm its contract manufacturer is in compliance, too. As such, there are some specific questions own-label distributors should ask to ensure they are distributing cGMP compliant dietary supplements.
Raw Material Sourcing
1. Are the raw materials and packaging components acceptable for use?
Make sure the raw materials come from suppliers that can be qualified under the Part 111 regulation. This will involve conducting audits and testing of suppliers raw materials as applicable. Problems in this area can cause ongoing supply interruptions or possible product adulteration. Do not use unstable raw materials since this could affect product shelf life. Conduct an adequate evaluation of dietary ingredients and technical ingredients, including scientifically valid identity testing. Plant- and animal-sourced ingredients often require extra attention to ensure they meet purity and potency specifications and are free from contamination. Regarding Prop 65 contaminants, some ingredients can be more problematic then others and require additional testing.
All packaging components should be suitable to protect the product from tampering and for the storage conditions the product will be subject to, while being inert to the product itself. Packaging materials that come in contact with the product need to be free of filth and potential contaminants. Verify companies supplying packaging materials that are in direct contact with the finished dietary supplement are knowledgeable about the 21 CFR regulations that apply to those components.
2. Will the labels cause the product to be misbranded or possibly recalled?
Labels and labeling issues cause more regulatory and legal action against products than all other cGMP matters. Ensure product labels have been reviewed by an expert in labeling regulations and laws that impact supplements. Labeling regulations are quite extensive, with primary label regulations for dietary supplements found at 21 CFR 101.36. However, additional labeling regulations for conventional foods also apply, principally found in 21 CFR 101 and elsewhere.
Claims and claims substantiation and having submitted to FDA the required 30 day notification are areas to focus on during establishment inspections. When using FDA-approved health claims, confirm the wording follows what is required for the specific nutrient; its worthwhile to be familiar with the general requirements for health claims found at 21 CFR 101.14. Labeling issues include the required format, layout, font size/type and information.
Here are some points to consider when reviewing the labeling:
- Statement of identity (name of the dietary supplement) on the principal display panel (PDP)
- Net quantity of contents statement (amount of the dietary supplement) on PDP.
- Nutrition labeling, Supplement Facts, on information panel.
- Ingredient list, on information panel.
- Name and place of business of the manufacturer, packer or distributor on information panel; complete domestic address or phone number.
- Warning statements, required, and also company created.
- Use directions.
- Expiration date (optional).
- Control / part / label version numbers.
- Storage conditions.
- UPC barcode.
- Made in the U.S.A. statement.
- Website address.
- Country of origin.
- Artificial flavors.
- PHENYLKETONURICS: CONTAINS PHENYLALANINE.
- Organic claims.
- Structure/Function Claims and Disclaimer.
- FDA-approved Health Claims.
- Nutrient Content Claims.
- Counterfeit protection measures.
3. Is my company ready for an FDA cGMP inspection?
During an FDA inspection, the area of focus for Part 111 cGMP compliance can be quite extensive, typically taking a few to several days. This will include a thorough inspection of the facility, operations, components, quality control (QC), written procedures, documentation/record keeping, etc. The inspection also includes an intensive series of questions that detail each subpart of the cGMP rule. Of particular importance is whether all employees have completed cGMP training. Such a program should include a general overview of Part 111, and subparts and sections related to appropriate operations, including inspecting and approving suppliers.
Don't wait to implement a compliance program until FDA conducts an inspection. Too often companies put off cGMP compliance until an FDA inspection, which can lead to enforcement actions and being thrust into a costly panic mode to catch-up on Part 111 compliance activities. Do have a contract manufacturing agreement that clearly delineates the Part 111 compliance obligations. In general, Own Label Distributors are responsible for the operations they are directly involved with, but should also conduct audits to confirm their contract manufacturers cGMP compliance.
Don't put off conducting onsite inspections of contract manufacturing facilities, and have written records to prove to FDA inspectors this was undertaken on a regular basis. Do check to determine whether the contract manufacturer has been inspected by FDA for Part 111 CGMP compliance. Proof of FDA compliance can be indicated in Establishment Inspection Reports, and cGMP certifications issued by the state of business operations.
Don't ignore the importance of written procedures, documentation and record keeping obligations. Do have written procedures required for your operations, and make sure the contract manufacturer has them as well. Part 111 requires establishing and following a number of written procedures, as specified in the various subparts of the rule, for example:
- Fulfilling the requirements for personnel.
- Cleaning the physical plant and pest control.
- Fulfilling the requirements for equipment and utensils, including calibrating instruments and controls used in manufacturing or testing a component or dietary supplement; calibrating, inspecting and checking automated, mechanical and electronic equipment; and maintaining, cleaning and sanitizing, as necessary, all equipment, utensils and any other contact surfaces that are used to manufacture, package, label or hold components or dietary supplements.
- The responsibilities of quality control personnel, including written procedures for conducting a material review and making a disposition decision and for approving or rejecting any reprocessing.
- Fulfilling the requirements for components, packaging and labels and for product that you receive for packaging or labeling as a dietary supplement.
- Laboratory operations, including written procedures for the tests and examinations conducted to determine whether specifications are met.
- Manufacturing operations.
- Packaging and labeling operations.
- Holding and distributing operations.
- Fulfilling the requirements for returned dietary supplements.
- Fulfilling the requirements for product complaints.
Don't forget the documentation/record keeping. Documentation/records required by the Part 111 rule are quite extensive. Which of the following examples concerns your operations or your suppliers operations related to dietary supplement manufacturing, packaging, holding and distributing?
- Documentation of training, including the date of the training, the type of training and the person(s) trained.
- Documentation, either in individual equipment logs or in the batch record.
- Documentation of any calibration, each time the calibration is performed, for instruments and controls used in manufacturing or testing a component or dietary supplement.
- Written records of calibrations, inspections, and checks of automated, mechanical, and electronic equipment.
- Documentation of the controls used to ensure equipment functions in accordance with its intended use.
- Documentation of the specifications established.
- Documentation of qualification of a supplier for the purpose of relying on the supplier's certificate of analysis (CofA).
- Documentation for why meeting in-process specifications, in combination with meeting component specifications, helps to ensure the dietary supplement meets the specifications for identity, purity, strength, and composition; and for limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch of the dietary supplement.
- Documentation for why the results of appropriate tests or examinations for the product specifications selected for testing ensure the dietary supplement meets all product specifications.
- Written documentation, at the time of performance, that QC personnel performed the review, approval or rejection requirements by recording the date that the review, approval or rejection was performed and the signature of the person performing the review, approval, or rejection.
- Documentation of any material review and disposition decision and follow-up.
- Receiving records (including records such as CofA, suppliers' invoices and suppliers' guarantees) for components, packaging and labels and for products received for packaging or labeling as a dietary supplement.
- Documentation, at time of performance, that the requirements for components, packaging, labels and product that is received for packaging or labeling as a dietary supplement were performed.
- The master manufacturing record.
- The batch production record.
- Documentation, at time of performance, that laboratory methodology is followed and the results of testing and examination.
- Records of product distribution.
- Any material review and disposition decision on a returned dietary supplement.
- The results of any testing or examination conducted on a returned dietary supplement to determine compliance with product specifications.
- Documentation of the reevaluation by QC personnel of any dietary supplement that is reprocessed and the determination by QC personnel of whether the reprocessed dietary supplement meets product specifications.
- A written record of every product complaint that is related to GMP. Also, be aware of requirements related to serious adverse event reporting.
Becoming cGMP compliant can be overwhelming for companies new to the regulatory world, and have not yet been through an FDA inspection. Working with a contract manufacturer and consultants with cGMP compliance experience, in addition to hiring qualified personnel, is vital for passing FDA inspections and avoiding warning letters and enforcement actions that can disrupt business operations and may lead to incurring avoidable liabilities.
Vince Paternoster is the president of NutriSport Pharmacal , a custom contract developer, manufacturer and packager of all types of dietary supplements, with experience in developing and manufacturing a variety of controlled-release dietary supplement tablets and capsules. Contact NSP at (888)703-3300, (973)209-7200 or [email protected]