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FDA and dietary supplement specifications
 
Q: How do we create dietary supplement specifications that will meet FDA expectations?
 
 
A dietary supplement's manufacturing specifications are a set of defined parameters and associated acceptance criteria that produce a finished product with the desired characteristics and quality. In June 2007, the FDA published 21 CFR Part 111, which established cGMP requirements for dietary supplements. Since then, manufacturers have struggled to understand and comply with these requirements regarding specifications development.
 
Over the past 10 years, this lack of understanding has led to some common citations in FDA Warning Letters related to the lack of or incomplete:
  • Raw material specifications, such as for dietary ingredients, excipients, process aids, or coating materials, that address identity per 21 CFR Part 111.70(b)(1) as well as purity, strength, composition, and limits of potential contaminants per 21 CFR Part 111.70(b)(2).
  • Specifications for in-process controls in the manufacturing process per 21 CFR Part 111.70(a) that address all of these same criteria of identity, purity, strength, composition, and limits of potential contaminants.
  • Specifications for finished products per 21 CFR Part 111.70(e) to include identity, purity, strength, composition, and limits of potential contaminants and packaging and labeling specifications per 21 CFR Part 111.70(d), (f), and (g).
 
Specification development
When developing specifications, you must consider and evaluate together the product formulation, proposed product label and labeling, manufacturing process, and test methods to be employed as early as possible. This may mean working with contracting partners such as contract manufacturers, co-packers, and contract laboratories to determine the acceptable range for each quality attribute and assess it properly. Gathering information about any material that's important to the quality of a finished product is also critical.
 
You must create written specifications; manage them in a controlled system, with tracked and monitored revision histories; and ensure that the quality department always reviews and approves them. The FDA requires these specifications for each raw material, packaging and labeling component, and finished product.
 
To prevent a product from being misbranded, the finished product must meet at least 100 percent of all nutrient claims declared on the label's Supplement Fact Panel (SFP) through its best-by or expiration date per 21 CFR Part 101.9 under the Nutritional Labeling and Education Act (NLEA). To ensure that the product is not adulterated, it must be consistently and reliably reproducible so that the customer receives the same-quality product every time, ultimately ensuring that it meets the identity, purity, strength, composition, and contaminant sections of the requirement outlined in 21 CFR Part 111.
 
Component specifications
Finished dietary supplement products commonly include both dietary ingredients—as defined in 201(ff) of the Food, Drug, and Cosmetic Act and claimed on the SFP—and nondietary ingredients—such as excipients, capsules, and coating materials. Per 21 CFR Part 111.70(b), you must establish component specifications for identity, purity, strength, and composition as necessary and limits on those types of contaminants that might adulterate or lead to adulteration of the finished batch. When building component specifications, you should clearly define or consider the typical relevant attributes, which include types of ingredients, ingredient forms, component sourcing, and acceptance criteria from the material supplier. You should use a reliable certificate of analysis (C of A) from a qualified supplier to help identify all applicable attributes.
 
Develop a written component specification for each attribute per 21 CFR Part 111.95 and include:
  • Identity specifications per 21 CFR Part 111.70(b)(1);
  • Information about qualified and approved supplier(s);
  • Material receipt, inspection, and sampling activities;
  • Limits on contaminants per 21 CFR Part 111.70(b)(3);
  • Assays, if applicable;
  • Strengths or concentrations;
  • Acceptance criteria with minimum and maximum ranges; and
  • A copy of the supplier's C of A that may include the following physical or chemical properties: color; density/particle size; plant species, such as botanicals; pesticides; odors; residual solvents; and storage conditions.
 
In-process specifications
You must establish in-process specifications for each point, step, or stage of your manufacturing and packaging processes. These specifications must focus on verifying material composition through a series of physical tests and examinations, such as in-process checks and metal detection. You can meet these specifications by developing a comprehensive Master Manufacturing Record (MMR) per 21 CFR Part 111.210 that the quality department reviews and approves. The MMR should establish:
  • In-process controls to demonstrate that the manufacturing and/or packaging processes are in a state of control and that you can meet finished product specifications;
  • Steps for executing in-process checks that include sampling plans and intervals, methods of metal detection, and an assessment of potential contaminants;
  • Definitions of components and finished products and of packaging and labeling specifications;
  • Acceptance criteria and testing methods to monitor the process; and
  • Documentation of results generated from all tests and examinations in a batch production record for every batch.
 
Packaging and labeling specifications
Packaging components are container closure systems and materials that may come into contact with a finished product, including desiccants, cotton, pouches, lids, outer cartons, labels, and inserts. For packaging and labeling components, written specifications should include information about the approved/qualified suppliers; the name and description of the item; and physical attributes, such as material type, size, dimensions, and color.
 
You can obtain the physical attributes and item descriptions from a reliable, qualified supplier's C of A. Additional packaging and labeling considerations include, but aren't limited to, the following items:
  • Quantity per unit and quantity to be packaged;
  • Front and back labeling requirements and date and lot code requirements; and
  • Label roll specifications and the quality department's label approval.
 
Keep in mind that you must develop packing specifications for every packing configuration of finished products. Set process and control specifications within the MMR and set a requirement that employees perform a visual examination for each batch. Also, the labels themselves must comply with NLEA, and you must establish a label specification, sometimes known as the master label.
 
Finished-product specifications
You must establish the identity, purity, strength, composition, and contaminant limits for each finished batch of dietary supplements. The finished-product specification must provide the details of testing requirements for a finished batch; identify all dietary ingredients on the SFP; and determine additional requirements of minimum and maximum acceptance criteria.
 
A claimed SFP ingredient must meet at least 100 percent of the label claim to meet the NLEA requirements. You may set release specifications at a higher percentage to account for any needed overage amounts formulated into the product to ensure that you meet the 100 percent requirement through the product's expiration or best-by dates. Before you make an overage determination, formulators must consider the finished product's composition, ingredient degradation, applicable upper intake limits (UL), and anticipated storage and handling conditions throughout the product's life cycle.
 
To determine whether you are meeting one or more product specifications, you must test or examine either every finished batch or a subset of finished batches identified through sound statistical sampling, such as a skip-lot or reduced-frequency testing plan.
 
Whatever method you choose, you must outline the testing scheme in detail. Document any exemptions from verification as described in 21 CFR Part 111.75 and provide a detailed justification for why you couldn't perform the verification, together with supportive scientific evidence.
 
Testing
Test methods designated on all specifications must be scientifically valid and can be a visual examination, such as an organoleptic or a macroscopic, microscopic, chemical, or microbiological analysis, or a combination of several of these.
 
Testing requirements must include methods that will:
  • Unequivocally identify the material or product received from suppliers;
  • Assess microbiological purity and meet other purity requirements;
  • Determine the strength and concentration of a dietary ingredient;
  • Evaluate the physical composition of ingredients; and
  • Identify any potential contaminants.
 
You can obtain recognized test methods from compendial sources such as US Pharmacopeia (USP) monographs, AOAC International, the Food Chemicals Codex (FCC), and the National Formulary (NF) as well as scientific published journals and/or your own product development team. You can use these sources as a starting point in determining an appropriate method, but you also must provide data demonstrating that the method is scientifically valid for the materials or products being tested. Manufacturers usually deploy multiple tests and examinations to ensure that the specifications meet the requirements of 21 CFR Part 111.75 and 21 CFR Part 111.320.
 
These compendial sources provide recommended acceptable ranges, but you must also consider data from your own product manufacturing and product stability history.
 
If you need further assistance, you can work closely with a qualified supplier(s), an accredited third-party laboratory, and/or qualified consultants to help with specification development.
 

 
Tamika Cathey is an independent consultant at EAS Consulting Group, Alexandria, VA. EAS specializes in FDA regulatory matters, helping domestic and foreign pharmaceutical, dietary supplement, and biologics firms comply with applicable laws and regulations.
 
Do you have a question for our experts? Send your questions to pwright@cscpub.com, and we'll have an expert answer them.
May 6, 2019
 
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