Instant GMP Compliance Series -Better Compliance through Master Manufacturing Records
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FDA inspections are increasing every year and they have published the results on their website. 50% of dietary supplement manufacturers are not in GMP compliance and 1 in 4 dietary supplement companies have received a warning letter which could result in a significant enforcement action such as halting production and distribution. Many of these producers received citation because they were not using Master Manufacturing Records.
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Instant GMP Compliance Series -Better Compliance through Master Manufacturing Records
- 1. InstantGMP Compliance Series for Dietary Supplements Better Compliance through Master Manufacturing Records
- 2. Background • Dietary Supplements are orally ingested products that contain an ingredient that is intended to supplement the diet • Not controlled by the FDA until 2007 • By 2010 all manufacturers or distributors of dietary supplements had to be in compliance with cGMP requirements • Now 1 in 4 manufacturers inspected by FDA receive Warning Letters Electronic cGMP Manufacturing Execution System
- 3. GMP for Dietary Supplements • FDA requires compliance with Good Manufacturing Practice (GMP) in manufacturing, packaging, labeling, or holding operations • Packaging and labeling has to be done per the master manufacturing record • Meets specifications for identity, purity, strength, composition and limits on contaminants Electronic cGMP Manufacturing Execution System
- 4. GMP for Dietary Supplements • Demonstrate that product has been manufactured, packaged, labeled, and held under conditions to prevent adulteration • Does not apply to dietary ingredients. • All requirements for cGMP compliance are the FDA’s “Final Rule” on dietary supplements Electronic cGMP Manufacturing Execution System
- 5. Highlights of DSHEA Final Rule • Applies to anyone who manufactures, packages, labels, or holds products • Establishes requirements for personnel, physical plant and grounds, and equipment and utensils • Requires written procedures (SOPs) • Requires specifications Electronic cGMP Manufacturing Execution System
- 6. Highlights of DSHEA Final Rule • Requires a quality control unit to ensure the quality of a dietary supplement • Requires master manufacturing records for each unique formulation and unique batch size • Requires a batch production record for each batch Electronic cGMP Manufacturing Execution System
- 7. Basics of cGMP Manufacturing • Instructions and procedures are clear and unambiguous • Manufacturing processes are clearly defined and controlled • Facilities designed to minimize cross-contamination and mix-ups • Operators are trained • Records demonstrate that all required steps were taken • Deviations investigated and resolved Electronic cGMP Manufacturing Execution System
- 8. Master Manufacturing Record • Must prepare and follow an MMR for: – Manufacturing – Packaging – Labeling • One MMR for each unique formulation and each batch size • Ensures uniformity in the finished product from batch to batch Electronic cGMP Manufacturing Execution System
- 9. MMR Must Include: • Name of the product • Strength • Concentration • Bill of Materials • Complete list of components • Weight or measure of each component • An equipment list with proper cleaning checked Electronic cGMP Manufacturing Execution System
- 10. Example MMR Cover Page
- 11. MMR Bill of Materials
- 12. MMR Must Include: • Written instructions for each step • Specifications at each step where control is necessary • Procedures for sampling • Where one person adds components, another person verifies the addition • Theoretical yield at each step where control is needed • Expected yield when manufacturing is completed Electronic cGMP Manufacturing Execution System
- 13. Definitions • Theoretical Yield = Quantity of product to be made • Actual Yield = Total quantity of product measured at the end of manufacturing a batch • Percent Yield = Actual Yield / Theoretical Yield X 100 • Percent Loss = 100 – Percent Yield Electronic cGMP Manufacturing Execution System
- 14. Process Control System • Covers all stages of manufacturing, packaging, labeling, and holding • Makes sure product is packaged and labeled as specified in the master manufacturing record • First step is to use high quality components with well-defined specifications • Avoids risk of making adulterated product Electronic cGMP Manufacturing Execution System
- 15. Master Record Storage/Retention • Length of time product complaints are likely to arise • Generally 2 years after date of distribution (not date of manufacture) • If shelf life dating is used, 1 year past the shelf life date • Packagers and labelers that return the product to the manufacturer for distribution do not need separate records Electronic cGMP Manufacturing Execution System
- 16. Master Record Storage/Retention • Records are the backbone of a quality system • FDA must have the means to examine them during an inspection • If microfilming is used, a suitable reader must be available • If electronic, must meet 21 CFR Part 11 requirements Electronic cGMP Manufacturing Execution System
- 17. Master Records Made Easy • InstantGMP makes managing Master Manufacturing Records easy • MMRs collaboration, review and signoff can be done on-line through its web portal • Version control is automatic • Part of an electronic cGMP Manufacturing Execution System Electronic cGMP Manufacturing Execution System
- 18. Benefits of Electronic Manufacturing • More efficient than manual systems • Shrink or eliminate redundant processes and forms • Trim time and overhead costs • Reduce errors, omissions and deviations • Provide opportunities to reorganize and update processes • Increases throughput, quality and margins Electronic cGMP Manufacturing Execution System
- 19. Thank You For Visiting! Additional presentations and videos on cGMP Manufacturing and Dietary Supplements are located in the Resource Center at: www.instantgmp.com
Editor's Notes
- Welcome to the GMP compliance Series for Dietary Supplements, a presentation courtesy of InstantGMP. This slideshow provides insight into the regulation of Master Manufacturing Records and how improving them will ensure a higher level of compliance in dietary supplement manufacturing plants.
- Up until 2007, anyone could make and sell dietary supplements such as vitamins or herbal products without any oversight from the FDA. In 2007 the FDA started phasing in cGMP compliance requirements for the largest manufacturers. By 2010 all manufacturers or distributors of dietary supplements had to be in compliance with cGMP requirements. Once the FDA started inspecting these manufacturers, they recorded observed infractions on FDA Form 483. If the problems were not addressed in a timely manner, companies are issued a more serious Warning Letter. Now 1 in 4 manufacturers inspected by FDA receive Warning Letters. We bring you this GMP Compliance Series in the hope that providing education on the most common issues will help companies become more diligent and avoid the hassles of being shut down by the FDA.
- The FDA issued the Good Manufacturing Practices for dietary supplements to ensure that these products will be safe for the ultimate consumer. The FDA requires compliance with cGMPs in manufacturing, packaging, labeling, or holding operations for dietary supplements. Any manufacturing, packaging and labeling has to be done according to a master manufacturing record. The components and final products have to meet specifications for identity, purity, strength, composition, and limits on contaminants.
- Each company has to demonstrate that their product has been manufactured, packaged, labeled, and held under conditions to prevent adulteration. It is important to note that dietary ingredient manufacturers do not have to follow cGMP rules. The full set of requirements for cGMP compliance are in the FDA’s “Final Rule” on dietary supplements.
- The Final Rule of the Dietary Supplements Health and Education Act applies to persons who manufacture, package, label, or hold dietary supplements. This rule establishes requirements for personnel, physical plant and grounds, and equipment and utensils. It requires written standard operating procedures (SOPs) for equipment, sanitation, manufacturing operations, quality control, packaging and labeling, and product complaints. It also requires that specifications are set and met in the production and process control systems
- The Final Rule requires a quality control unit to ensure the quality of a dietary supplement. Where most firms fail to comply is in meeting MMR requirements. Master manufacturing records need to be written for each unique formulation and each unique batch size and followed every time a dietary supplement batch is made.
- The basics of cGMP manufacturing are straight forward. Manufacturing instructions and procedures have to be clear and unambiguous. Manufacturing processes need to be clearly defined and have controls at each critical step of the process. Manufacturing facilities must be designed to minimize cross-contamination and mix-ups. Operators must be trained and have documentation of that training . Records have to demonstrate that all required manufacturing steps were taken and that any deviations to the written process were investigated by the QC unit and resolved before the batch was dispositioned.
- In order to comply with the cGMP requirements, an MMR must be written and followed for manufacturing and packaging of a batch, or labeling of a product received from a supplier. Master manufacturing records need to be written for each unique formulation and each unique batch size and followed every time a dietary supplement batch is made. This will facilitate ensuring uniformity in the finished product from batch to batch.
- The Master Manufacturing Record should include the name of the finished product, the strength, the concentration and the weight or measure of each dietary ingredient and each component. It must have a Bill of Materials or a complete list of components and dietary ingredients that will go into the product. This will keep employees from adjusting the amounts of ingredients from memory or based upon ratios learned from other employees. Master Records should specify the equipment to be used and require that equipment cleaning is checked to make sure equipment use will not result in contamination of the batch.
- This is an example of the information that is typically included on the cover page of a Master Record. Details include the client product code, part number, drug name, and batch size. A cover page should provide information about a manufacturing or production record that defines a product so that it is easily identifiable or differentiated from similar products; for example formulation ID, unit and drug strength.
- This screenshot shows a common way of presenting a Bill of Materials. Material name, part number, quantity and unit are displayed. Version numbers are use useful in cases where materials are ordered from different vendors or used in different quantities for different formulations.
- Each Master Record must have written instructions including specifications for each step or stage in the manufacturing process where control is necessary to ensure quality. Whenever one operator performs a step, a second person is to verify the action was done according to the record in real time. A statement of theoretical yield at each controlled step of the manufacturing process as well as the expected final yield must be written in the Master Record. The Record must also include procedures for sampling to ensure quality.
- Theoretical yield is the quantity that would be produced at any appropriate step of manufacturing or packaging based upon the quantity of components or packaging to be used, in the absence of any loss or error in production. Actual Yield is the total quantity of product measured at the end of actually manufacturing a batch. The Percent Yield is calculated by dividing the Actual Yield by the Theoretical Yield and multiplying by 100. The Percent Loss is 100 minus the Percent Yield.
- A process control system covers all stages of manufacturing, packaging, labeling, and holding. It ensures the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record. The first step in ensuring safe, high quality products is to use high quality components that meet well-defined specifications. It is optimal to test materials before their use in a product rather than risk making an adulterated product or contaminating manufacturing equipment.
- The record retention time for records related to CGMP requirements correlate with the length of time that product complaints are likely to arise. The required time is 2 years beyond the date of distribution. Using the date of manufacture is not recommended. The date of manufacture does not necessarily mean the product’s availability in the marketplace. A product could be held for some time before getting to store shelves. A more accurate calculation uses the date of distribution. For products with a shelf life date, the records must be kept for 1 year past the shelf life date. Packagers and labelers that return the product to the manufacturer for distribution are not required to keep separate records.
- Records are an indispensable component of cGMP. The FDA must be able to inspect Master Manufacturing Records and other supporting documentation during their inspections. If reduction techniques such as microfilming are used, suitable reader and photocopying equipment must readily available to them. If you use electronic manufacturing or documentation systems, these must meet 21 CFR Part 11 requirements for Electronic Documentation and Electronic Signature.
- InstantGMP provides access to complete control over your Master Manufacturing Records, making it easy to get into or to stay in compliance. You can collaborate on the development of Master Records, have them reviewed by production and quality staff and signed off with digital signatures all on-line through a common web site. The Master Manufacturing Records are just one part of a complete electronic cGMP Manufacturing Execution System. Learn more at www.InstantGMP.com.
- There are many reasons that companies will want to adopt an electronic manufacturing system. They are more efficient than manual systems. For example, they can shrink or eliminate the redundant process and forms that occur in manual systems. They can trim time and costs compared to manually compiling and reviewing documentation. They can reduce errors, omissions and deviations. Probably the most important advantage is that a transition to an electronic system can provide opportunities to reorganize and to update processes to make the whole plant work better. All of these benefits together will result in increased throughput, quality and margins.
- This presentation is just one of many articles and videos available on cGMP compliance for Dietary Supplements. Find them in the Resource Center at www.InstantGMP.com.