Technical Training Courses In-Plant...
(Technical training for the pharmacuetical, beverage, food, nutritional supplement, nutraceutical, and related industries! Courses can be specifically developed, or, the following outlines can be altered to meet the educational needs of your manufacturing, processing and packaging operation.)
TechSourceŽ offers numerous training courses related to the pharmaceutical (and similar manufacturing), beverage and food industries. If you wish, we can customize a course to meet your specific needs. Let us know what you want, and we'll help you develop a course to meet your training criteria. Successful training programs are critical and are an integral part of a world-class operation. They are vital to the success of your company! Without them, production time is lost, inefficient work practices become the norm, and your bottom-line is negatively impacted. The following is a listing of some of our more popular In-Plant course outlines, these can be adjusted to meet your company's requirements...
Total Productive Maintenance - Course Summary:
Maintenance should be a continuous ongoing process, because well maintained equipment will always make you a good quality product. Provide your personnel with the vital tools and knowledge they need to improve and implement the necessary changes to your equipment to always produce a high-quality product. Your market place is demanding high-quality from its suppliers and it is crucial to your organization to make 100% quality a reality. Maintenance is a vital component in reaching and maintaining your high standard for quality. This course will provide your personnel with the tools and knowledge they need to be successful!
- Quick Changeover Technology - Course Summary:
Changeover and Startup Technology is one of the most important challenges facing manufacturers today! Proper implementation provides an endless return-on-investment for your company. In this course you'll learn the principles and methods that enable you to drastically reduce your changeover and startup times. You will learn how to free-up machine capacity, reduce inventories, increase throughput and better meet your customer's demands for product and lower costs!
- How Changeover Time Reduction Fits Into Your Company Improvement Plan:
The 3 keys and HOW to focus your employees on these fundamentals - Recognizing the 4 areas of improvement - Why yearly improvement goals are not enough, and how creating a definition of changeover time is what gets results - The relationship of SUTR to job security - How to create an understanding that changeover time is wasted time, and help employees to recognize value-added time
- Understanding Costs and How to Reduce Them:
Why the need to focus on inventory costs and the reduction possibilities due to changeover time and lot size reduction - Understanding quality costs and why they are important - How to ensure your efforts get the desired results in cost reduction - Developing the relationship between demand and lot size and how to establish a strategy that gets results - A complete cost/benefit that clearly identifies the "return-on-investment" for any changeover time reduction investment
- Cycle Time Reduction and Its Impact on Your Business:
How to conduct an analysis of your cycle-time and plan for improvement - How to find and eliminate bottlenecks - Understanding "demand-based manufacturing" and getting started with the effort through "changeover time reduction" - Eliminating the queue time and the impact of change - Understanding the benefits of total cycle time reduction
- Organizing for Changeover Time Reduction with a Results Orientation:
Defining the reduction task and creating the charter - Identifying the functions that contribute to reduced changeover time - Focusing efforts and how to proceed in changeover time reduction - Developing "champions" and training employees to reduce changeover time - How to establish the basis of "Changeover Time Reduction" and getting employees comfortable with the effort - Eliminating flow contraints and the 7-Steps to completion - Understanding the importance of safety during changeover and meeting all contractual obligations
- Implementing the Proven Method of Changeover Time Reduction:
How to get a complete videtapeing of your changeover - Understanding the documentation format and how to use it - Developing categories and creating a "Pareto Chart" of your changeover(s) - Moving to the external, eliminating and reducing the time it takes to do a current changeover
- Case Study in Changeover Time Reduction:
This is a thorough step-by-step example of changeover time reduction providing employees with an understanding as to how to slash your changeover time(s) - Students go through all the steps of documentation: time netting, activity classification and brainstorming to develop the results - Each group presents their results and determines the amount of reduction possible - How to get reults-focused problem solving applied to your changeovers
- Identified Areas for Improvement:
How to externally locate, organize and maintain all change parts - Applying a checklist that will result in a 50% reduction in changeover time - The effect of maintenance and changeover time reduction - Organizing and implementing improvements that reduce clamping and adjustment problems encountered in changeovers - How to make automated improvements and determine their cost effectiveness
- Establishing Measurement Control for Changeover Time Reduction:
Implementing performance measurements that energize to success - Establishing an average non-value changeover time measurment - Achieving stretch goals - Measures of improvement necessary that provide return-on-investment - Possible department and cell measurements - How to close the results and apply developed results
- Review of Existing Equipment Changeovers and Recommendations:
A class tour of your facility with the instructor to find changeover opportunities for improvement(s) - The instructor will utilize a video camera to capture the opportunities and use that/those video(s) in the review session as an analysis tool - After an extensive "evaluation tour", the class will reconvene to review the recommendations and conduct a final question and answer session
Advanced Quality Methods - Course Summary:
At times, we need to go beyond standard quality practices and implement more sophisticated tools in order to attain our quality goals. This course will introduce your personnel to more advanced quality methods to help attain higher standards of quality for your operation(s).
- Understanding Total Productive Mainenance:
Historical development of TPM - Focusing on TPM - Why TPM? - Goals of TPM - 5 elements of TPM
- Equipment Effectiveness:
The total maintenance system - Devpartmental involvement - Employee involvement - Common work groups
- Increasing Profits Through Equipment Effectivenss:
Productivity - Quality - Cost - Material delivery - Morale
- Problem Solving and TPM:
14 Step problem solving - Symptom development - Root cause analysis - Developing solutions - Implementation
- Equipment Investment:
Maintenance free design - Design to life cycle costs - Equipment flexibility - Technical support and training
- Equipment Life Cycle:
Life cycle cost - Life span - Startup failure - Operational failure - Deterioration
- 6 Obstacles to Equipment Effectiveness:
Breakdowns - Startup - Minor stoppages - Reduced speed - Process defects - Low yields
- Eliminating Equipment Failures:
Cleaning - Procedures - Part replacement - Improve design - Operator skill level
- Equipment Measurements:
Operating rate - Performance efficiency - World-class performance - Uptime vs. downtime - Minor stoppages - Major stoppages
- Breakdown Counter-Measures:
Daily maintenance practices - OEM recommendations - Machine overhaul - Mean Time Between Failure Analysis (MTBFA)
- Getting TPM Started in Your Company:
Management commitment - Communications - Education and training classes - Organize to promote TPM - Maintenance charts at the machines
- Company Involvement:
Top management - Middle management - Cell teams - Operators - Support areas
- TPM Development Team:
Team makeup - Up-front steps - Providing leadership - Goals and objectives - Implementation
- 7 Elements of a Maintenance Program:
Cleaning - Eliminate causes- Standards of lubricating - Inspection standards and procedures - Cross departments - Organization of responsibility - Ownership and improvement
- The Roles Involved in TPM:
TPM team - Maintenance - Maintenance personnel - Flow down - Natural work areas - Cell teams - Local TPM teams
- Elements of a Maintenance Program(s):
Motivation - Ability - Working conditions - Team information
- Steps to Implement TPM:
Machine identification - Power source identification - Lock-out procedure - Daily maintenance system - OEM maintenance system - MTBFA system - Development format - Critical machine listing - Next steps - Implementation of program planning
Statistical Process Control - Course Summary:
Quality is an expected attribute of our products. This is mandated by law and demanded by our customers. An overview of "Total Quality" will be addressed including the 3-keys to its success and how to focus your employees on them, recognizing your customer's expectations, and the areas needed for improvement. Attendees will learn about Statistical Process Control (SPC) and are provided with the tools to successfully implement an SPC program!
- Team Formation:
Definitions - Organization - Team Building
- Understanding Quality Issues:
Total Quality Management (TQM) - Customer expectations - Glossary of terms - Steps involved in "Advanced Quality Methods" (AQM)
- Understanding Statistics:
Type(s) of data - Variation(s) - Customer tolerance - Loss function
- Problem Identification:
Data sources - Pareto chart - Analyzing data - Key characteristics
- Gage System Evaluation:
Gage "Repeatability and Reproducibility" (R&R) - Gage R&R flowcharts - Gage R&R forms
- Data Collection:
- Data Organization:
Frequency distribution - Histograms - Physical and chemical interactions: mechanisms of residue elimination, residue elimination from surfaces, what services can the cleaning agent supplier offer you, trade secrets
- Variable Control Charts:
X-Bar and R-Charts - IX-MR Charts - Interpreting control charts - Run rules
- Process Capability:
Capability studies - Cp - Cpk - Process fallout
- Part Family Charts:
X-Bar and R - IX-MR - Cp and Cpk for Part Family Charts
- Attribute Control Charts:
np Charts - P Charts - C Charts - U Charts
- Identifying Problem Causes:
Cause and effect diagrams - Brainstorming
- Process Mapping:
Process flow chart - Process flow diagram - Picture chart
- Decision Making Using Data:
Problem solving - Implementation
Water Systems Technology - Course Summary:
The design of a USP System, whether for Purified Water, WFI or even Clean/Purified Steam requires a thorough understanding of the following: the supply source water chemistry; the user's requirements and needs including instantaneous and total consumption; a working knowledge of available technologies; and a familiarity with the regulatory, validation and other guideline requirements or standards which will govern the system. The requirements to become technically astute is growing and the complexity of every function demands skilled, educated, alert and competent individuals in every position. This course addresses the factors that need to be examined when a company considers a system's design and its supporting equipment.
- Understanding Statistics in Their Application to SPC:
Understanding the statistics that apply to process control is provided in laymen's language so that everyone in your company will be able to understand and relate to it - Examined are the data and how it applies to your operation(s) - Created is an understanding of variation and how it connects your employees to improvements in the process - A clear understanding of the differences between tolerance and specification is presented along with an overview of how losses are incurred in your plants
- Gage System Evaluation:
A complete presentation addressing "Gage Repeatability and Reproducibility (Gage R&R)" including the steps involved in conducting Gage R&R - Included are the flowchart(s) that follow, the forms for documentation and analysis, and then the results are addressed
- Initial Data Collection:
Employees begin to work the statistical process - Employees look at collected raw data and in a class exercise put that data into a Run Chart - Emphasis is placed on the accuracy of their data - Recommednations are made by the instructor on areas where they should begin to collect data for their jobs
- How to Organize Data:
This section addresses "Frequency Distribution" and "Histograms" - Students develop a Histogram on their collected data - An understanding of how to analyze the histogram to determine if the process demonstrates normal distribution and what to do if its not normally distributed
- Variable and Attribute Control Charting:
An in-depth study of X-Bar and R-Bar along with a case study will provide you with a complete understanding of their application to your operations(s) and how to interpret the charts - The 4-Run Rules are addressed, understood, and explained as to how you utilize them in your plant - The terms In-Control and Out-of-Control are explained by utilizing many examples - Examples and case studies are presented in "P" and "U" attribute control charting
- Process Capability:
A complete guide to conducting studies based on Cp and Cpk are presented along with tables to determine the process fallout once you know the capability of your process
- Process Mapping:
Need for documenting the process - The 3-Tools needed to document your process and to ensure that its improvements are followed - This includes Process Flow Charting, Flow Diagraming, and Picture Charting
- Decision Making Using Data:
SPC is a powerful tool when used properly - The goal is to collect, organize, analyze the data and then conduct problem solving using the collected data - You will be given first-hand exmaples and learn to make decisions using your statistical data and how that information applies in the problem solving process - The conclusion is the implementation of improvements that result in capability improvement
Cleaning Validation: Pharmaceuticals and Related Industries - Course Summary:
This is a "DROP-DEAD ISSUE" on a inspector's check list and is a major area of focus for the FDA. Areas that are frequently cited include the following: inadequate equipment cleaning and validation protocols; cleaning methods for common equipment that aren't validated; inadequate sampling and testing of surfaces; residue limits for potential contaminants are not established; specificity and sensitivity of analytical methods are not established; not testing of residues in solvents used in BPC production; and these are only a few of the FDA's concerns! Cleaning validation is only one part of a good cleaning program. A minimal program should include at least the following six components: cleaning validation, training, monitoring of cleaning, revalidation if necessary, documentation and analytical methods validation.
This course was originally developed for pharmaceutical manufacturers. However, companies that manufacture vitamins, nutritional supplements, food processors and many other industries have attended this training. If you have cleaning issues, this training will be very valuable to you and your personnel!
- Water System Design Process:
Characterization of Feed Water - Contaminants in the water - Dissolved inorganics - Feed water analysis parameters - Major cationic calcium carbonate equivalents - Major anionic calcium cabronate equivalents - Effects of bicarbonate alkalinity on carbon dioxide and on pH - Determine the required quality - Examples of user customized water specifications - Determining required quantities - Additional design considerations - Developing flow schematics
- System Design and Equipment:
System Design and Critical Information - Quality requirements - Temperature requirements - Total volume - Instantaneous demand - Usage duration - Consistency of demand - Available feed - Number of use points - Use point requirements - Loop sizing - Equipment selection issues - Basic guidelines - Equipment specification comment - Feed interruptions - Reserve and redundancy - Sanitization - Control issues - Facility issues - Cost constraints
- Unit Operations:
Holding and Distribution - Major components - Demand concerns - Quality concerns - demand considerations - Quality Considerations - Sanitization - Monitoring - Operation and maintenance - Validation(s)
Materials of Construction - Specification issues - Tube and Fitting - Non-metallic - Stainless steels - Sanitary Finishes - Specification issues - Terminology - Comparative example(s) - Valves - Manufacturing methods - Other considerations
KEPCO data for surface measurement(s)
- Sanitary Tubing Installation and Machine Welding Specifications:
Scope - Purchasing - Receiving - Handling - Storage - Instruction and certification - Component preparation - Surface preparation - Purging - Alignment and tacking - Documentation - Inspections - Erection - Chemical cleaning - Component - Passivation log sheet - Weld inspection check - Weld schedule
Multimedia Depth Filtration - Water softening, water softener and softener operation(s) - Activiated carbon filtration and its advantages and disadvantages - Purification technology - Typcial polishing processes, polishing technology and select system components
- Deionization in Water Production:
Ion Exchange - Major Cationic Calcium Carbonate equivalents - Cation exchange resin - Strong acid cation exchange resin - Anion exchange resin - Strong base anion resin - Weak base anion resin - Separate bed deionizer - Mixed bed deionizer - Chemical regeneration requirement - Mixed bed regeneration cycle - In-place regenerable deionizers - Off-site regenerated deionizers - Hot water sanitizable deionizers - Ion exchange resin bacteria control methods - Ion exchange resin pretreatment - Electrodeionization - Ion exchange membrane in CDI - Ion exchange resin in CDI - Ion exchange resin in applications - The ion pure CDI process - H-series CDI performance RO feed - Sanitization procedures - CDI operation costs - Water recovery - RO/CDI water recovery - Silica - TOC - Limiting pH values in pure water - Effect of bicarbonate alkalinity and carbon dioxide on pH
- Reverse Osmosis Applications:
Reverse Osmosis (RO) - Basic RO system schematic - RO membrane operating parameters - RO rejects and rejection - RO pretreatment parameters and requirements - Scale control methods for RO pretreatment requirements - RO Membrane Types - cellulose acetate, polyamide, thin film composite, polysulfone - Conventional membrane - Pharmaceutical grade membrane - RO membrane parameters, rejection, pretreatment requirements - Membrane system design guidelines - 80 GMP, TWO pass, RO system with interstage feed pump - Cleaning system flow diagram - Cleaning procedures
- Hot Water Sanitizable RO and UF Membrane for Use in USP Water Systems:
What is sanitization (disinfection)? - Mehtods for membrane sanitization - What is sterilization and methods for membrane sterilization - Potential USP application(s) for hot water sanitizable RO - Hot water sanitization advantages and heat sanitization disadvantages - Hot water RO cartridge construction - Conventional and sanitary RO cartridges - RO heat sanitization - Lab test(s) - Lab evaluation(s) and test apparatus - Lab's evaluation(s) and test condition(s) - Lab data and permeate flux - Lab data and membrane rejection - Hot water product flow in sanitization mode - Lab data results summary - Hot water sanitization procedure - RO heat sanitization - The 4 heat sanitization methods - Separate sanitization skid - Sanitization built into RO - Using system break tank - Existing hot water supply - Hot water sanitizable RO system - RO for WFI - Hot water sanitizable RO - Potential applications for UF - Pyrogen removal methods - Bacteria control methods - Polymeric UF pyrogen control - Ceramic UF - Pyrogen control - Operating parameters and limits - Cleaning procedure(s) - sterilization procedure(s) - Endotoxin reduction
- Sample P&ID Development:
Review Drawings - 16 drawings are reviewed that apply to water systems - Students are encouraged to bring in thier own drawings
Water Systems - Material procurements and handling - Erection - Equipment - Distribution loop - Cutting and deburring - Purging - Weld coupons - Production welding - Inspection and testing - Assembly - Insulation - Hydrotesting - Cleaning - Passivation - Startup - Testing - Validation - Training
- Fundamentals of Passivation:
What does passivation mean? - Characteristics of the oxide film - The prerequisite to establishing a uniform oxide film - Methods available for establishing a passive surface - Reasons to passivate - Mechanism of oxide breakdown - Benefits of and steps involved in passivation - Chemicals used to passivate - Chemical application method - Tests for cleanliness and passivity - Passivation references - Establishing effective procedures - Passivating solutions - Soils in existing systems - Where does rouge come from? - Facts of rouge - Where to find evidence of system rouging - Modified passivation procedures - Coping with combined, new and existing systems
Packaging Facilities: FDA Expectations for Pharmaceuticals and Related Industries - Course Summary:
With a rash of mislabled products, medication errors and numerous recalls, the FDA is looking more closely than ever at packaging facilities. Especially, contract packaging facilities. This course addresses the primary issues the FDA focuses on when visiting a packaging facility!
- Regulatory Requirements:
Cleaning: Equipment cleaning and regulatory requirements - GMP amendments for contamination - Regulatory requirements of cleaning - Court decisions - U.S. vs. Barr Laboratories - Regulatory requirements and pre-approval inspections - Pre-approval inspections 7-year summary - International regulatory aspects - What happens if you ignore regualtory requirements - Examination of typical 483s - Warning Letters, etc.
- Specific Needs of Different Subparts of the Pharmaceutical Industry:
Unique qualities of various industries - Manufacturers of bulk pharmaceutical chemicals (BPCs) and the production scheme of BPCs - Manufacturers of clinical trail materials (CTMs) - Medical device manufacturers - Biotechnology products - Food supplements - Excipients, etc.
- Cleaning Approaches and Strategies:
Cleaning programs in the pharmaceutical industry - Cleaning approaches and strategies and where does cleaning "fit" in the overall company validation master plan? - "Worst Case" approaches
- Cleaning Validation Documentation:
Parts of the protocol and what we use them for, and after the protocol is prepared, what is next? - Critical parameters of cleaning
- Sampling Methods:
Types of sampling - Swab - Rinse - Solvent - Direct surface monitoring - Coupon sampling - What are the hot spots and critical sites?
- Analytical Methodology:
Analytical methods for cleaning and modes of detection - Analytical methods validation - Visual and gravimetric analysis - pH - Conductivity/resistivity - FDA 483 observations - Light microscopy - Titration - Spectroscopic techniques - Thin layer chromatography - Capillary zone electrophoresis - Enzyme linked immunosorbant assay - High performance liquid chromatography - HPLC with evaporative light scattering detector - ELSD response - Ion chromatography - Total Organic Compound (TOC) - TOC analysis of how does it work - Why is it so prevalent - A typical process description for TOC and its technology - Use of TOC in combination with swabs - TOC data conversion - How to deal with the nonspecific nature of TOC - Manufacturers
Types of residues - Other possible contaminants and special contaiminants - Physical and chemical interactions - Mechanisms of residue elimination - Residue elimination from surfaces - What services can the cleaning agent supplier offer you? - Trade secrets
- Limits for Cleaning Validation:
Questions for the pharmaceutical companies - Questions for the FDA inspectors - What is clean enough depends on several factors - Industry - How the product is used - Nature of the manufacturing equipment - How good are the cleaning procedures - Nature of the primary product - Nature of other products made in the same equipment - What is the shared common equipment surface area - Assay detection limits - Concept of hot-spots and critical sites - Some approaches for setting limits - Concept of safety factors - Basing limits on limit of detection - Allowing not more than a certain concentration of contamination in subsequent products - The Lilly approach - A sample calculation for the various carryover possibilities, we could calculate a "Worst Case" calculation, or, calculate a liquid products calculation such as for syrups and injections, etc. - Establish limits for BPC precursors, by-products and cleaning agents, develop a sample calcualtion for
chemical precursors and intermediates - Sampling and analytical considerations - Maintenance of "Good Cleaning Programs" after the completion of "Validation"
- Cleaning Methods and Agents:
Do you know what a cleaning agent is? - Modern cleaning agents - Commercial - Custom - Typical and what else to select from? - Which ingredient in a cleaning agent should the analytical focus be on? - Physical removal processes - Solvent based cleaning - Theory of contamination - Survey referred to by Rohsner and Serve
- Current Trends:
Regulatory - Cleaning methods - Analytical
- Cleaning of BPC/APIs:
The manufacturing of BPCs - Equipment cleaning - Dosage form manufacturing involves physical changes - BCP manufacturing involves both physical and chemical changes - Potential contaminants - Regulatory aspects and requirements - FDA 483 comments - Organic solvents and cleaning agents - Limits - Multiple level approach to BPC cleaning - Two product scheme contamination possibilities - Levels 1, 2, 3 and 4 cleaning and what is the difference between the levels - FDA guidance on limits, strategy for calculating limits for BPCs and limit calculations based on toxicity - Limits calculations based on the NOEL approach - Step 1, limits calculations - Step 2, calculate NOEL from LD50 data - Step 3, calculate ADI or calculate ADI from NOEL, and - Step 4, calculate MACO from ADI
Validation: Basic Principles for Non-Sterile Pharmaceutical and Related Industries - Course Summary:
This course introduces you to the basic principles necessary for the establishment of an effective process validation program. This is a nuts-and-bolts course that addresses validation(s) for equipment, manufacturing processes, documentation, analytical and automation issues, cleaning validation and revalidation. This is an excellent technical introductory course for "NON-STERILE" process validation!
- Current Packaging vs. the Future of Packaging:
Quotes - Child-resistent closures - Medication errors - Smart packaging - Shortage of pharmacists - And finally, so this means?
- FDA Expectations for Packaging Facilities:
What will bring the FDA inspector to your packaging facility - Actual FDA visits - FDA expectations - Packaging Warning Letters - The letter goes on to say... - 483 comments
- Validation of the Packaging Process:
Perspectives - What you need to run a successful validation program - Packaging validation policies - Master validation plan - Some preliminary requirements - What must be validated before the packaging can be validated? - Learn the packaging process - Overall validation strategy - Basic approach - The problem?
- Defining Validation:
Type of validation - Prospective validation - Concurrent validation - Retrospective validation - Finished product audit(s) - Before getting started, learn the packaging process - Protocol contents - How are acceptance criteria established? - What are the critical parameters? - Critical parameters for a tablet blister line? - First, evaluate the process of the tablet blister line - Evaluate other important factors involved in the tablet blister line - Good references for blister packaging - Critical parameters for a liquid filling bottle line? - Evaluate the process of the liquid filling bottle line - Identification of other parameters that need to be recorded - Critical parameters for an ointment(s) and cream(s) tube filling line? - Evaluate the process of the tube filling line - Evaluation of the critical parameters that need to be identified - Sealing temperature(s) - Test function for seal temperature(s) - Critical parameters and test functions for tablet blisters - Critical parameters and test functions for bottles that are liquid filled - Critical parameters and test functions for an ointment(s) and cream(s) tube filling line
- After Validation is Completed:
Other aspects of packaging requiring validation - FDA 483 comments (labeling equipment) - Challenge testing - Criteria(s) for revalidation - Question(s) if the packaging line is moved? - Question PQ? - Question change parts? - Question portable equipment? - Question the new packaging line? - Question the IQ/OQ? - Question non-GMP function(s)? - Question the principles of computer validation? - Question the revalidation? - Question the first three-lots for PQ?
- Cleaning Validation for Packaging Facilities:
Where does packaging fit into your organization's overall validation program? - Is it one continuous process? - Why is the packaging area so important regarding cleaning? - Must the cleaning of all areas of packaging be validated? - The packaging line - Approaches to cleaning validation for packaging
- The Train Approach:
Decision(s)? - If we take a "Worst Case Approach" - Another matrix to help select the worst case product - What is/are the clean limit(s)? - Total limits for all equipment? - Total limits for Solid Dosage forms based on medical dosage - Calculations - Limits based on medical dosage - Calculations - Surface areas of various pieces of equipment in the train - Limits for the filler - Total limits for liquid dosage forms based on medical dosage
- Considering Packaging to be a Separate Operation from Manufacturing:
Once you've calculated a limit you must sample the machine - Sampling methods - Analytical sensitivity - Recovery, a special analytical issue for swab samples - Visual examination of equipment - FDA 483 citation - Sampling locations - Examples of critical sites - Limits of critical sites - Cleaning agent issues - Disinfectants - Cleaning of non-contact surfaces - Microbial issues for packaging cleaning non-sterile products - New methods for monitoring microbial levels - Luminator T - Microbial issues for packaging cleaning sterile products - Disposable equipment - 483 comments
- Know Your Facility and What Your Regulatory Agency Wants from YOU!:
Many companies over-validate their operation(s) with the hopes of placating the FDA - Know what your regulatory agency wants from you? - This will help you validate only what needs to be validated and prevents you from spending your money needlessly!
Troubleshooting: Cleaning Issues for Dietary and Nutraceutical Manufacturing Facilities - Course Summary:
The FDA/law defines a dietary supplement as: "a product taken by mouth that contains a "dietary ingredient" intended to supplement the diet. In order for an ingredient of a dietary supplement to be a "dietary ingredient," it must be one, or, any combination of the following substances: vitamin, mineral, an herb or other botanical, an amino acid, a dietary substance used by man to supplement the diet by increasing the total dietary intake (e.g., enzymes or tissues from organs or glands) or, a concentrate or metabolite, constituent or extract. A new "dietary ingredient" is one that meets this definition for a "dietary ingredient" and was not sold in the U.S. in a dietary supplement before October 15, 1994. This training places emphasis on the primary reasons for the closing of manufacturing facilities, cGMPs, warning letters, regulatory compliance, the HACCP process, microbiological issues, and addressing the needs and concerns as expressed and identified by the FDA!"
- History and Development of Current Good Manufacturing Practices Regulations (cGMPs):
Their interpretation and how they lead to the development of the concepts of process validation and cleaning validation - Demonstrated is how process and cleaning have become such hot issues and the subject of intense investigation by the FDA - Included are excerpts from the book "The Jungle" by Upton Sinclair, the publication generally given credit with leading to the formation of the FDA
- Equipment Validation:
Basic objectives of validation - Validation vs. qualification - Installation of equipment/Installation Qualification (IQ) - Operation of equipment/Operational Qualification (OQ) - Preventive maintenance programs - Testing at the vendor's site prior to shipment - Validation of packaging
- Manufacturing Process Validations:
Product orientation - Retrospective validation - Concurrent validation - Prospective validation - Process Qualification (PQ) - Indentification of critical process parameters (and the special aspect of coated products) - Development of a Master Plan (What is the overall plan?) - What will be required to release product? - How will critical parameters be evaluated? - Sampling plan - What testing will be done (physical, chemical, or microbiological testing)
- Documentation Issues:
Approvers of protocols and finished packages - What does a signature mean? (bringing proper expertise to bear on issues) - Who should review what?
- Analytical Issues:
Methods Validation - Accuracy - Precision - Ruggedness - Linearity - Specificity - Limit of detection (LOD) - Limit of Quantitation (LOQ) - Change control for analytical methods
- Automation Issues:
Automation vs. manual processes - Validation of hardware - Validation of software - Security - What are the objectives?
- Cleaning Validation:
Importance of scientific rationales - Importance of cleaning as an issue in Pre-Approval Inspections (PAIs) - Grouping of products to determine worst-case - Setting of limits and acceptance criteria
What "Triggers" revalidation? - Correlation with annual product review - Change control
- Reasons for the FDA to Close a Facility:
Manufacturing violations - Dirty equipment, not properly cleaned - Not maintaining proper records - Incorrectly labeled products - Not reporting ill effects from product(s) - History of violations - Inadequate HVAC - Manufacturing deficiencies, etc.
- FDA Regulatory Expectations for Cleaning:
"Title 21 Part III" Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements - Review of FDA warning letters
- cGMP for Dietary Supplements:
"Hygenic Practices - Wearing outer garments to protect against contamination - Washing hands and removing jewerly - Wearing and maintaining impermeable gloves - Wearing hairnets and beard covers - Not storing clothing in areas where components and products or equipment are exposed - Another statement in the hygenic practices section: "Taking any of the precautions necessary to protect against the contamination of components, dietary supplements, or contact surfaces with microogranisms, filth or any other extraneous materials, including perspiration, hair, cosmetics, chemicals, and medicines applied to the skin."
- Subpart C - Physical Plant and Grounds:
Preventive maintenance - Holding of materials and cleaning agents - Water supply and plumbing, "avoid being a source of contamination, "provide adequate floor drainage", and "do not allow backflow" - Trash disposal and hazardous waste
- Subpart D - Equipment and Utensils:
"You must establish and follow written procedures for calibrating instruments, "maintaining, cleaning, and sanitizing, as necessary, all equipment, utensils, and other contact surfaces" - "You must use equipment and utensils that are of appropriate design, construction, and workmanship to enable them to be suitable for their intended use and to be adequately cleaned and properly maintained" - "You must use equipment and utensils of appropriate design and construction so that use will not result in contamination of components or dietary supplements with lubricants, fuel, coolants, metal or glass fragments, filth , contaminated water or any other contaminants" - "All equipment and utensils you use must be installed and maintained to facilitate cleaning, corrosion resistant, made of nontoxic materials, maintained to protect components and dietary supplements"
- Construction Requirement:
"Equipment and utensils you use must have seams that are smoothly bonded or maintained to minimize accumulation of dirt, filth, organic material, particles of components or dietary supplements, or any other extraneous materials or contaminants"
- Refrigerators and Freezers:
"Each freezer, refrigerator, or other cold storage compartment you use to hold components or dietary supplements must be fitted with an indicating thermometer, termperature measuring device, or temperature recording device that indicates and records or allows for recording by hand the temperature accurately within the compartment"
- Compressed Air:
Compressed air or other gases you introduce mechanically into and onto a component, dietary supplement, or contact surface or that you use to clean any contact surface must be treated in such a way that the component, dietary supplement, or contact surface is not contaminated - "You must maintain, clean and sanitize, as necessary all equipment, utensils, and any other contact surfaces used to manufacture, package, label, or hold components or dietary supplements" - Disassembly requirments, "equipment and untensils must be taken apart as necessary for thorough maintenance and cleaning and sanitizing" - Drying requirment, "you must ensure that all contact surfaces, used for manufacturing or holding low-moisture components or dietary supplements, are in a dry and sanitary condition when in use. When the surfaces are wet-cleaned, they must be sanitized, when necessary, and thoroughly dried
before subsequent use." - "If you use wet processing during manufacturing, you must clean and sanitize all contact surfaces, as necessary, to protect against the introduction of microorganisms in components or dietary supplements. When cleaning and sanitizing is necessary, you must clean and sanitize all contact surfaces before use and after any interruption during which the contact surface may have become contaminated."
- Continuous Production and Campaigning:
"If you use contact surfaces in a continuous production operation or in consecutive operations involving different batches of the same dietary supplement, you must adequately clean and sanitize the contact surfaces, as necessary. - "You must clean surfaces that do not come into direct contact with components or dietary supplements as frequently as necessary to protect against contaminating components or dietary supplements." - "Cleaning compounds and santizing agents must be adequate for their intended use and safe under their conditions of use."
- Subpart E - Requirement to Establish a Production and Process Control System:
"You must establish limits on those types of contamination that may adulterate or may lead to adulterations of the finished batch of the dietary supplement to ensure the quality of the dietary supplements."
- Regulation Conclusions:
They are very general in nature - They contain a lot of interpretative wording - There is no mention of validation, either process validation or cleaning validation in the regulations
- Warning Letters:
They are sent to the owner or CEO of the company - They usually start out with "your company is in violation or failed to comply with the cGMP Regulations for Dietary Supplements (21 CFR Part 111) - They state that "these violations cause your products to be considered adulterated..." - It states specific violations - Gives you 15 working days to respond in writing
- Warning Letters Issued in Final Quarter of 2011:
12 letters were issued to dietary supplement companies - 79 letters sent for cGMP violations - 44 letters were issued to food companies - 18 letters were issued to medical device companies - 5 were issued to pharmaceutical companies
- Review of Information in a Recent Warning Letter:
Issued January 30, 2012 to a dietary supplement company - "Your Batch Production Records (BPR) must include the date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producting the batch, or a cross-reference to records, such as individual equipment logs, where this information is retained." - "You failed to hold components and dietary supplements under conditions that do not lead to the mix-up, contamination, or deterioration of components and dietary supplements." - "You stored a glove used for cleaning, a hammer, and four different raw materials in labeled polybags together within a box labeled "xxxx componenet. The glove and hammer could contaminate your componenets. In addition, storing different components together in a box could confuse employees and lead to a mix-up of components. Various components in labeled polybags were stored together in the same box bearing a handwritten list of the components contained inside the box. Storing
different components together could cause contamination. The SOPs entitled "Packaging Line Approval", "Issuance and Documentation of Labeling Materials", "Equipment Use Logbook", Cleaning Procedures for the Lakso Slat Counter", and "Corrective Actions by QA/QC Department" include many tasks that are to be performed by quality assurance personnel. However, you have no quality assurance personnel." "The SOP entitled "personnel disease control, hygeine, and gowning" states that rubber gloves will be worn at all times during production activities. However, our investigator observed an employee touching component xxxx for placing in bottles with bare hands." " The SOP entitled "Personnel Training" states personnel engaged in the manufacturing, inspection/testing, processing, packaging, labeling, holding and distribution of the nutritional products will be trained to the extent that they understand the essential requirements for performing their job funtions. The SOP further states that the training will be
documented on the attached training record form. However, you have failed to document any training. You have failed to make and keep records for the documentation of training, including the date of the training, the type of training, and the persons trained." - "The plumbing in your physical plant is not of an adequate size of design to avoid being a source of contamination to components, dietary supplements, water supplies, or any contact surfaces, or creating an unsanitary condition."
- What is Next?:
Be vigilant and thorough in all you do - Determine where you are now and where you want to be (i.e., in regulatory compliance) - Many refer to this process as "GAP Analysis" - GAP Analysis should look at facilities, training, documentation, warehousing, and quality programs - How do you bridge that gap - "FDA estimates that compliance with the final rule will cost the dietary supplement industry $86 million annually and deliver benefits of $218 million in fewer recalls and reduced liability. The American Herbal Products Association suggests that the actual benefit may be $21 million and the cost of compliance could be at least $700 million.
- How do you get There - Hazard Analysis and Critical Control Points (HACCP):
Risk Assessment - Not all deficiencies are equally serious - HACCP is a risk assessment currently used in the food and pharmaceutical industries
- HACCP Process:
Conduct a hazard analysis - Determine the critical control points - Establish critical limits - Establish monitoring procedures - Establish corrective actions - Establish verifications procedures - Establish record keeping and documentation procedures
- HACCP Process for Cleaning:
Find the "worst case product" - Most potent - Least soluble - Most difficult to clean - Most allergenic (review complaint files, annual product review notes, talk with QA, etc.) - Most prone to support bacterial growth
- Microbial Concerns:
Focus of the regulations - Materials are often nature sourced and do support microbial growth - Prepare a rationale for controlling microbial growth, group products and processes that do vs. those that do not support microbial growth - Microbiological Attributes from USP monograph number 2023, "Microbiological process control, control of the bioburden of raw materials, and control of the manufacturing process to minimize cross-contamination are necessary to guarantee acceptable microbial quality in the final dosage forms. Because nonaqueous or dry dosage forms do not support microbial growth because of low water acitivity, the microbial quality of such articles is a function of the microoragnisms introduced through ingredients or during processing. This document also contains tables containing the micro limits for the various types of raw materials, excipients, and botanical products as well as for other nutritional products which do not contain botanicals."
- Grouping of Products Matrix:
Group 1, solid dosage forms (tablets, caplets, powders) - Group 2, true solution liquids - Group 3, suspensions - Group 4, semi-solids (ointments, creams) - Finds the worst case in each group and verify the cleaning procedure for that product
Product vs. Cleaning Parameters Matrix - Product vs. Equipment Matrix - A Master Plan will help you in the short and long term - Most of the deficiencies are usually very basic observations, i.e., cGMP - Documentation - Training - Plumbing
These and other courses are available for In-Plant training. Just let us know your training needs and we'd be more than happy to assist you!
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