Instant GMP Compliance Series - Improving Documentation
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The FDA enforces the Dietary Supplement Health and Education Act (DSHEA) law by inspecting dietary supplement manufacturers, packagers, labelers and holders for Current Good Manufacturing Practices (cGMPs) compliance. One of the main issues they found was the lack of proper documentation. This presentation provides an overview of the documentation that is needed for cGMP compliance.
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Instant GMP Compliance Series - Improving Documentation
- 1. InstantGMP Compliance Series for Dietary Supplements Documentation of cGMP Procedures
- 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 2
- 3. GMP Problems with Documentation • Most common citation in FDA Warning Letters – inadequate documentation • Lack of detail on written procedures • Inadequate control of specifications • Failure to perform review and disposition • Insufficient or non-existent Master Manufacturing Records • Batch records did not follow the Master • QC did not properly disposition batch Electronic cGMP Manufacturing Execution
- 4. Why Documentation Is Important • Impossible to stay in compliance without written documentation • Used to train quality and operations staff • Assures consistency in how processes are followed • Enforces uniformity and quality • if adulteration occurs, records will show the source of the material so that its use can be stopped Electronic cGMP Manufacturing Execution
- 5. Why FDA is Hot on Documentation • They want records to show: – What was manufactured – If controls were in place to control quality – What deviations occurred – That corrective actions were effective – If a product should be recalled – That cGMPs were followed • In the FDA’s mind – “If it wasn’t documented, it wasn’t done” Electronic cGMP Manufacturing Execution
- 6. Improving Documentation • First rule of cGMP Compliance: “Document what you do and do what you document” • FDA guidances on cGMP have the details • Interpretation is allowed – just write up what you intend to do as SOPs • Then follow them Electronic cGMP Manufacturing Execution
- 7. Records Are Required For: 1. Personnel 2. Sanitation 3. Calibration of instruments and controls 4. Calibration and inspection of automated, mechanical, or electronic equipment 5. Maintaining, cleaning, and sanitizing equipment and utensils and other contact surfaces 6. Water used as a component 7. Production and process controls Electronic cGMP Manufacturing Execution
- 8. Records Are Required For: 8. Quality control 9. Components, packaging, labels and product received for packaging and labeling 10. Master manufacturing and batch production 11. Laboratory operations 12. Manufacturing operations 13. Packaging and labeling operations 14. Holding and distributing operations 15. Returned dietary supplements 16. Product complaints Electronic cGMP Manufacturing Execution
- 9. Most Common FDA Citations • Inadequate documentation of cGMP procedures • No Master Manufacturing Records created • Batch production records had inadequate information or didn’t follow the master • No documentation that specifications were set • No in-process control • Deviations occurred without corrective action or documentation • Suppliers and vendors were not qualified Electronic cGMP Manufacturing Execution
- 10. Master Manufacturing Records Must Have: • Complete list of components (Bill of Materials) • Weight or measure of each component • Identity and measure of each dietary ingredient • Theoretical yield at each step where control is needed • Expected yield when manufacturing is completed • Written instructions for each step of the manual operations • Specifications at each step where control is necessary • Procedures for sampling • Where one person adds components, another person verifies the addition • An equipment list with proper cleaning checked Electronic cGMP Manufacturing Execution
- 11. Batch Production Records Must Have: • Identity of equipment and processing lines used • Date and time of the maintenance and cleaning, or a cross-reference to logs • Identity and weight or measure of each component • Actual yield and percent theoretical yield • Documentation that finished dietary supplement meets specifications Electronic cGMP Manufacturing Execution
- 12. Batch Production Records Must Have: • Unique batch number for each batch • Proof that quality control reviewed the BPR and dispositioned the batch • All results which were obtained during the operation • Reference to the physical location of the label • Manufacturing steps for tablets and capsules to prevent metal or other foreign materials from equipment getting into the batch Electronic cGMP Manufacturing Execution
- 13. Specifications Needed For: • Components • In-process production • Labels and packaging • Finished batch of dietary supplement • Product that you receive from a supplier for packaging and labeling • Packaging and labeling for the finished dietary supplement Electronic cGMP Manufacturing Execution
- 14. In-Process Controls • Must monitor the steps where control is necessary to ensure quality • Determine whether the in-process specifications are met • Controls include COA from qualified vendors • Dietary ingredients need identity testing • Use scientifically valid method for each specification • Quality control personnel must conduct all reviews and make disposition decisions Electronic cGMP Manufacturing Execution
- 15. Deviations • Triggered by any unanticipated occurrence could result in adulteration • May not reprocess a batch that deviates unless approved by Quality • Quality must conduct a material review • Then make a disposition decision • Corrective and Preventative Actions (CAPA) needed for deviations Electronic cGMP Manufacturing Execution
- 16. Supplier/Vendor Qualification Programs must include: • A program for periodic audits and re- qualifying of vendors • Qualification of all suppliers including components, ingredients, labels, etc. • Confirmation of vendor's test results and certificates of analysis Electronic cGMP Manufacturing Execution
- 17. Supplier/Vendor Qualification Programs must include: • Reviews of specifications, procedures, and lab controls • Assurance that all personnel affected by cGMP are trained • Regular review of vendor’s documentation • Calibrations and recalibrations performed by the equipment manufacturer if not done in- house Electronic cGMP Manufacturing Execution
- 18. How Long Must Records be Kept? • 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 Electronic cGMP Manufacturing Execution
- 19. How Must Records be Kept? • 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
- 20. SOPs Made Easy • InstantGMP maintains a complete set of manufacturing Standard Operating Procedures (SOPs) and Policies for cGMP manufacturing • Available as individual SOPs to supplement what you already have • Available as an entire set as a foundation for a complete quality system www.instantgmp.com/Standard-Operating-Procedures Electronic cGMP Manufacturing Execution
- 21. InstantGMP™ Find more videos on cGMP Compliance for Dietary Supplements in the Resource Center at www.instantgmp.com
Hinweis der Redaktion
- The staff at InstantGMP prepared the cGMP for Dietary Supplements Compliance Series of presentations to focus on good manufacturing practices and cGMP compliance for dietary supplements manufacturing. These are brought to you by our quality and manufacturing experts in the hope that it will help you avoid any cGMP compliance issues in your shop. This presentation will address the documentation of cGMP procedures.
- Dietary Supplements are orally ingested products that contain an ingredient that is intended to supplement the diet. Manufacturing of dietary supplements was not controlled by the FDA until 2007. At that time the Dietary Supplements Health and Education Act became law. It required all manufacturers or distributors of dietary supplements to be in compliance with cGMP requirements by 2010. Since then 1 in 4 dietary supplement manufacturers inspected by the FDA have received Warning Letters threatening to stop their operation if compliance issues are not addressed. This series was started to provide education and guidance for dietary supplement manufactures who want to improve their good manufacturing practices compliance.
- One of the most common failures cited by FDA inspectors in Warning Letters is lack of adequate documentation. The FDA wants to see details on how firms make and keep written procedures for specifications, Quality Control operations, Master Manufacturing Records, returned goods and equipment. The FDA cited manufacturers for failing to provide written documentation that specifications were set and that testing was completed before using a component or ingredient in a batch. In many cases, there were no written master manufacturing records (MMR) for each unique formulation of dietary supplements or the batch production records did not follow the Master Manufacturing Record. The FDA expects documentation to show that batches were properly made and that the quality control personnel performed their review and disposition of products at the time of manufacturing.
- There are many cGMP requirements for making and distributing good quality dietary supplement products. It would be impossible to stay in compliance if there were no written documentation and proof that each of the cGMP requirements were met. The production and quality staff can be easily trained and can stay in compliance if there are written procedures for them to read when they first start the job and that they can refer back to when they need a refresher. Without written procedures, the staff may not remember the correct way to do things or they may do the steps differently over time. Written procedures enforce uniformity and quality which is what consumers deserve and the FDA mandates. if adulteration of the dietary supplement occurs, the records will show the source of the material so that its use can be stopped.
- The FDA wants records that will show what is to be manufactured and whether the controls for identity, purity, strength, and composition and limits on contaminants and to prevent adulteration were effective. They also want records that will show whether and what deviations from control processes occurred and what corrective action were taken to assure that the corrections were effective. Records are needed to show whether batches of products with deviations should be recalled from the market. Good documentation ensures that CGMPs are being followed and you are making a quality product. In the FDA’s mind, “if it wasn’t documented, it wasn’t done”.
- How do you improve compliance? Our first rule of cGMP compliance is “Document what you do, and do what you document.” The FDA guidance documents on cGMP regulations has very detailed instructions on compliance requirements. You are free to interpret the guidance and write up your own processes. Just make sure you document how you will do each of the major functions of cGMP manufacturing. Once you have the documented your processes as Standard Operating Procedures, then follow them each time.
- The final rule of the Dietary Supplements Health and Education Act establishes the minimum manufacturing practices necessary to ensure that dietary supplements are manufactured, packaged, labeled, or held in a manner that will ensure the quality of the dietary supplements. Records are required for (1) Personnel; (2) sanitation; (3) calibration of instruments and controls; (4) calibration, inspection, or checks of automated, mechanical, or electronic equipment; (5) maintaining, cleaning, and sanitizing equipment and utensils and other contact surfaces; (6) water used that may become a component of the dietary supplement; (7) production and process.
- The FDA also spells out that records are needed for (8) quality control; (9) components, packaging, labels and product received for packaging and labeling; (10) master manufacturing and batch production; (11) laboratory operations; (12) manufacturing operations; (13) packaging and labeling operations; (14) holding and distributing operations; (15) returned dietary supplements; and (16) product complaints.
- The FDA inspection reports and Warning Letters are published and are available for review at the FDA web site. We have selected out the issues that are most commonly cited by FDA inspectors. Inadequate documentation of cGMP procedures Master Manufacturing Records were not created Batch production records had inadequate information or didn’t follow the master No documentation that specifications were set No in-process control because of inadequate in-process specifications Deviations occurred without corrective action or documentation Suppliers and vendors were not qualified We’ll go into a more detail on each of these issues and provide some suggestions on how you can avoid these pitfalls.
- Each Master Manufacturing Record (MMR) needs to include 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. Each MMR should also include: The weight or measure of each component to be used The identity and weight or measure of each dietary ingredient A statement of theoretical yield at each step of the manufacturing process where control is needed to ensure quality The expected yield when you finished manufacturing the dietary supplement Written instructions, including specifications for each point, step, or stage in the manufacturing process where control is necessary to ensure quality Procedures for sampling Written instructions for manual operations Where one person is to add a component and where another person is to verify the addition MMRs should specify the equipment to be used and require that equipment cleaning is checked to make sure its use will not result in the contamination of the dietary supplement.
- According to cGMP requirements, your BPR must include the following information: The identity of the equipment and processing lines used in producing the batch The date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross-reference to records, such as individual equipment logs The identity and weight or measure of each component and dietary ingredient used in the batch A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing Documentation that the finished dietary supplement meets its specifications
- Each Batch Record must have a unique number assigned to it, corresponding to a unique instance of producing a specific batch of a specific product. The Batch Production Record must include real-time documentation of steps performed. This includes the initials of the person responsible for weighing or measuring each component used in the batch, the initials of the person responsible for verifying the weighing step, the initials of the operator adding the component to the batch, and the initials of the verifier who witnessed the addition step. Batch records must have documentation of packaging and labeling operations including the unique identifier that is assigned to packaging and labels used, and the quantity of the packaging and labels used. The FDA requires Batch Records have documentation that Quality Assurance personnel reviewed and determined the disposition of the BPR. This includes documentation of approval or rejection of materials, reprocessing or repackaging, and final approval and release for distribution, or rejection the batch. Batch Production Records should show the actual results obtained during monitoring of tableting or encapsulating operations and inspections of the final product; this includes documentation of any instances of dented, discolored or possibly adulterated samples. Regulations require reference of correct labeling of the product to be part of the BPR including samples of any labels from the corresponding batch-specific labels in order to assure accuracy. Manufacturing processes for tablets and capsules should include the use of filters, strainers, traps, magnets, electronic metal detectors, or any other comparable means of preventing the inclusion of foreign materials from equipment or the environment in the product.
- You will need to establish specifications for components, in-process production, labels and packaging, the finished batch of dietary supplement, product that you receive from a supplier for packaging and labeling, and the packaging and labeling for the finished packaged and labeled dietary supplement.
- You must monitor the in-process points, steps, or stages where control is necessary to ensure the quality of the finished batch of the dietary supplement. This is done to determine whether the in-process specifications are met and to detect any deviation or unanticipated occurrence that may result in a failure to meet specifications. quality control personnel conduct all required material reviews and make all required disposition decisions You may test a subset of finished dietary supplement batches that the firm identifies through a sound statistical sampling plan for selected specifications rather than test every batch of the finished dietary supplement for every specification. Finally, quality control personnel must review and approve any exceptions from testing requirements
- A deviation can be an unanticipated event that occurs during production and could possibly result in adulteration of a component of a dietary supplement. Pre-planned deviations from the BPR may be written and approved as well. Deviations should be noted in the batch production record along with documentation that describes either the reasoning for the planned deviation or the investigation into the root cause of an unplanned event. Actions taken to correct the deviation and prevent a recurrence of the deviation must be identified. This information should be recorded in a Corrective Action and Preventable Action Register so trends can be identified and a record of resolution programs can be kept. The quality control unit will need to evaluate whether or not the deviation resulted in or could lead to adulteration of a component, dietary supplement, packaging, or label to ensure the quality of the product. A batch cannot be reprocessed or approved for distribution without QAU approval of a scientifically sound plan for acceptable in-process adjustments. Regulations prohibit the use of rejected ingredients unless the quality control unit determines that in-process adjustments are possible to correct the deviations or occurrence. Others may assist quality control personnel in gathering and considering information relevant to the review and decision, but Quality control personnel must approve or reject all processes, written procedures, controls, tests and examinations, and deviations.
- Each company must qualify all its suppliers including those who provide components, ingredients, labels, or any other controlled item/substance involved in manufacturing. A Vendor Verification Program should consist of: Periodic audits and re-qualification of vendor facilities to check for compliance and confirmation of the vendor's test results and certificates of analysis to ensure that COAs can be relied upon to be accurate.
- Audits of suppliers are required to cover all aspects of compliance including: -Reviews of specifications, procedures, and lab controls -Assurance that all personnel affected by cGMP are trained Regular review of vendor’s documentation Confirming calibrations and recalibrations are performed by the equipment manufacturer if not done in-house The FDA expects that supplement manufacturers will exceed old regulations in preparation for meeting new regulations as they become more stringent and include more technical reviews of specifications, procedures, and lab controls. With the FDA expecting a higher compliance rate in the future and increasing technicality of inspections, a higher demand for 3rd party cGMP auditors in the US is expected. The question is how do you prepare for FDA inspections and ensure that your facility is cGMP compliant? Here are some tips that can help you get ready for cGMP compliance inspections: Ensure all QA/QC and all other personnel affected by cGMP regulations are familiar with the sections of 21 CFR part 11 that apply to their department and ensure those personnel receive training on those requirements Finally, remember that compliance can only be found through due diligence and ensuring that you are aware of the requirements and are using industry resources available to you.
- The retention period for controlled records should correlate with the length of time that product complaints are likely to arise related to the manufacture of a dietary supplement. Such correlation will increase the likelihood that, if a problem with a dietary supplement is identified that may be associated with a violation of CGMP, the manufacturer can address the issue with proof in hand. The packaging date or “date of manufacture” does not necessarily indicate the availability of the dietary supplement product in the marketplace, it has no effect on the amount of time records must be kept. It is possible that such product could be held for a period of time after manufacture before entry into the marketplace and possible consumer consumption. A more accurate time period is calculated by the date of distribution. The final rule now requires a record retention period of 2 years beyond the date of distribution of the last batch of dietary supplements associated with those records, or 1 year past the expiration date. Packagers and labelers that return the product to the manufacturer for distribution are not required to keep separate records under this subpart.
- Records are an indispensable component of CGMP. The records required by this final rule provide the foundation for the planning, control, and improvement processes that constitute a quality control system. Implementation of these processes in a manufacturing operation serves as the backbone to CGMP. if you use reduction techniques, such as microfilming, you must make suitable reader and photocopying equipment readily available to us
- To make it easy for you to get into or to stay in compliance, InstantGMP has a complete set of manufacturing Standard Operating Procedures (SOPs) and Policies for available for cGMP manufacturing. You can choose individual SOPs to supplement what they already have or you can use the entire set as a foundation for a complete quality system.
- This presentation is just one of many articles and videos available on cGMP compliance for Dietary Supplements. You can access the rest at the Resource Center at www.InstantGMP.com.