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USP <1115> Bioburden Control of Non‐sterile Drug Substances and Products: Intent Implementation Products: Intent, Implementation and Impact Tony Cundell, Ph. D. Consulting Microbiologist Consulting Microbiologist Scarsdale, NY August 4, 2014 IVT Microbiology Week 1 Disclosures • The The opinions expressed in this presentation opinions expressed in this presentation are solely mine and not those of my former employer Merck & Co the USP Microbiology employer Merck & Co, the USP Microbiology Committee of Experts or my current consulting clients consulting clients. August 4, 2014 IVT Microbiology Week 2 IVT Microbiology Week IVT Microbiology Week • The The speaker wish to thank IVT program manager speaker wish to thank IVT program manager Curry Wilson, conference chair Karen Ginsburg, and event coordinator Kelly Carr for organizing this outstanding conference. • Congratulations. August 4, 2014 IVT Microbiology Week 3 Presentation Outline • The intention of the USP Microbiology Committee of Experts • Implementation of the USP Chapter Implementation of the USP Chapter • Expected impact of the new USP chapter <1115> • Extent of microbial contamination of non‐sterile drug products • Content of the USP Chapter <1115> • Risk hierarchy by dosage form Risk hierarchy by dosage form • Factors increasing microbial contamination risk • Drug substances • Pharmaceutical excipients • Drug Products • Role of Manufacturing Role of Manufacturing August 4, 2014 IVT Microbiology Week 4 What is the USP? What is the USP? • The U.S. Pharmacopeial p Convention Inc. is an independent standards organization, founded in 1820, empowered by the U.S. Federal Food, Drug, and Cosmetic (FD&C) Act as the official drug and Cosmetic (FD&C) Act as the official drug standard‐setting organization in the U.S. for drug p products. • The Pharmacopeial Convention publishes and maintains the United States Pharmacopoeia (USP), N ti National Formulary (NF), and USP Reference lF l (NF) d USP R f Standards and sets the quality standards for both drug products and pharmaceutical ingredients. gp p g August 4, 2014 IVT Microbiology Week 5 U.S. Pharmacopeia U.S. Pharmacopeia • Hard Copy Hard Copy August 4, 2014 • Electronic Electronic Copy Copy • May be download from the USP website: www.usp.org/usp‐ nf/offical‐text IVT Microbiology Week 6 USP Intention • The new USP Informational Chapter <1115> Bioburden Control of Non‐sterile Drug Substances and Products was published in the 2nd Supplement to USP37‐NF32 July 2014. What was the intent of the USP in publishing this chapter? USP in publishing this chapter? • In the absence of regulatory guidance, the USP has provided a pragmatic scientific approach to the provided a pragmatic scientific approach to the management of the microbial bioburden in non‐ sterile drug products in keeping with patient risk and gp p g p contamination control objectives based on risk management principles. August 4, 2014 IVT Microbiology Week 7 USP Intention USP Intention • The The chapter contains information on microbial chapter contains information on microbial control considerations in product development, routine manufacturing, equipment design and use, microbial assessment of the non‐sterile manufacturing environment, active measures for microbial control, and the overall management of a i bi l t l d th ll t f microbiological control program. • Note: It is an informational chapter and not an Note: It is an informational chapter and not an enforceable compliance document. August 4, 2014 IVT Microbiology Week 8 Presentation Outline Presentation Outline • The intention of the USP Microbiology Committee of Experts • Implementation of the USP chapter • Expected impact of the new USP chapter Expected impact of the new USP chapter <1115> 1115 • Extent of microbial contamination of non‐sterile drug products • Content of the USP Chapter <1115> Content of the USP Chapter <1115> • Risk hierarchy by dosage form • Factors increasing microbial contamination risk • Drug substances • Pharmaceutical excipients • Role of Manufacturing Role of Manufacturing August 4, 2014 IVT Microbiology Week 9 Industry Implementation Industry Implementation • How How should drug substance and drug product should drug substance and drug product manufacturers react to the publication of this chapter? • I would hope that they should adopt a more risk‐ based approach to bioburden control in non‐sterile drug development and manufacturing based on an understanding of what determines the presence of microorganisms in their manufacturing facilities and microorganisms in their manufacturing facilities and their persistence or proliferation in their drug products. products. August 4, 2014 IVT Microbiology Week 10 Expert Opinion Expert Opinion • David David Hussong, FDA CDER Microbiology Director, Hussong, FDA CDER Microbiology Director, stated: “For the microbiologist, this (quality initiatives) emphasizes the importance of process knowledge to replace reliance on testing samples of finished product. Avoiding microbiological adulteration yields a more reliable indicator of d lt ti i ld li bl i di t f quality, which agrees with the assertion that quality cannot be tested into the product ” cannot be tested into the product. August 4, 2014 IVT Microbiology Week 11 Industry Implementation Industry Implementation • Manufacturers Manufacturers should appreciate that whether should appreciate that whether microorganisms found in a non‐sterile product will be objectionable in that product depends their number and species, the product attributes, dosing regimen, route of administration, and targeted patient population. ti t l ti • Any environmental monitoring program would be risk based in terms of sample selection and risk‐based in terms of sample selection and frequency and would be used to confirm microbial control and would not be linked to product release. control and would not be linked to product release. August 4, 2014 IVT Microbiology Week 12 Presentation Overview • • • • • • • • • • • The intention of the USP Microbiology Committee of Experts Implementation of the USP Chapter Expected impact of the new USP chapter <1115> Extent of microbial contamination of non‐sterile drug products Content of the USP Chapter <1115> Risk hierarchy by dosage form Risk hierarchy by dosage form Factors increasing microbial contamination risk Drug substances Pharmaceutical excipients Drug Products Role of Manufacturing August 4, 2014 IVT Microbiology Week 13 Industry Impact Industry Impact • What is the expected impact of the USP chapter? at s t e e pected pact o t e US c apte • The expectation is there would be improved and cost‐ effective bioburden controls for non‐sterile drug products to a level consistent with patient safety. • This may reduce product recalls for microbial contamination. t i ti • Manufacturers will be able to benchmark their bioburden control programs against the bioburden control programs against the recommendations within the chapter and adjust their programs accordingly. August 4, 2014 IVT Microbiology Week 14 Presentation Outline Presentation Outline • The intention of the USP Microbiology Committee of Experts • Expected impact of the new USP chapter <1115> • Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug products • Content of the USP Chapter <1115> • Risk hierarchy by dosage form • Factors increasing microbial contamination risk • Drug substances Drug substances • Pharmaceutical excipients • Role of Manufacturingg August 4, 2014 IVT Microbiology Week 15 Microbial Contamination Microbial Contamination • The The contamination of marketed products with contamination of marketed products with objectionable microorganisms continues to be an infrequent but chronic problem for our industry. • There are the order of 20 U.S. recalls on non‐sterile products annually for microbial contamination. August 4, 2014 IVT Microbiology Week 16 What are Objectionable Microorganisms? What are Objectionable Microorganisms? They are defined by specific dosage forms. They include specified microorganisms, frank pathogens and opportunistic pathogens that are known from the clinical literature to cause known from the clinical literature to cause infection in the recipient via the route of administration or microorganisms that grow in the product overcoming the preservative system p g p y Also, they may include organisms associated with major recalls for microbial contamination If these microorganisms are present in the drug If these microorganisms are present in the drug product below the microbial limit, the batch would be rejected. August 4, 2014 IVT Microbiology Week 17 U.S. Congressional Hearings U.S. Congressional Hearings August 4, 2014 IVT Microbiology Week 18 U.S. Recalls • A recent U.S. survey reported 144 recalls composed of non‐sterile of non sterile branded pharmaceutical drug branded pharmaceutical drug products (5%), over‐the‐counter drug products ( (42%), cosmetics (31%), medical devices (14%) and ) ( ) ( ) dietary supplements (8% of the total recalls) for microbiologically‐related issues for the 7‐year period from 2004 through 2011 f h h • The survey highlighted that the majority of these recalls (72%) were associated with objectionable ll (72%) i t d ith bj ti bl microorganisms and not for exceeding the microbial enumeration limits (Sutton and Jimenez 2012) enumeration limits (Sutton and Jimenez, 2012). August 4, 2014 IVT Microbiology Week 19 Microorganisms Implicated Microorganisms Implicated • The The most frequently cited microorganisms in the most frequently cited microorganisms in the recalls were the Burkholderia cepacia complex (34 occurrences), unspecified fungal contamination (19 occurrences), Bacillus cereus (9 occurrences), Pseudomonas aeruginosa (6 occurrences), Eli b thki i Elizabethkingia meningoseptica i ti (5 occurrences), (5 ) Enterobacter gergovia (5 occurrences), Pseudomonas putida (3 occurrences), Pseudomonas Pseudomonas putida (3 occurrences) Pseudomonas spp. (2 occurrences) and Salmonella spp. (2 occurrences). ) August 4, 2014 IVT Microbiology Week 20 Burkholderia cepacia Complex Burkholderia cepacia Complex • The The prominence of the Gram prominence of the Gram‐negative, negative, oxidase oxidase‐ positive bacterium B. cepacia in non‐sterile product recalls is the result of it prevalence in water, metabolic versatility, and its resistance to many disinfectants and antimicrobial preservative systems. t • B. cepacia is a common opportunistic pathogen and infects cystic fibrosis sufferers infects cystic fibrosis sufferers. August 4, 2014 IVT Microbiology Week 21 Unidentified Fungi Unidentified Fungi • The The second most prevalent recall category was second most prevalent recall category was unidentified fungi. This reinforces that pharmaceutical microbiologists do a poor job identifying mold. • For further information see Cundell, A. M. 2013 Mold Contamination in Pharmaceutical Drug products and Medical Devices European Pharmaceutical Review 18 (6): 67 75 Pharmaceutical Review 18 (6): 67‐75 August 4, 2014 IVT Microbiology Week 22 Presentation Outline Presentation Outline • The intention of the USP Microbiology Committee of Experts • Expected impact of the new USP chapter <1115> • Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug products • Content of the USP Chapter <1115> • Risk hierarchy by dosage form • Factors increasing microbial contamination risk • Drug substances Drug substances • Pharmaceutical excipients • Role of Manufacturingg August 4, 2014 IVT Microbiology Week 23 Contents of the USP Chapter p • Introduction • Risk Hierarchyy • USP <61>, <62> and <1111> • US Regulatory Guidance Documents • Microbial Control Consideration During Product Development • Microbial Control Consideration During i bi l C l C id i i Manufacturing • Microbial Control of Drug Substance Manufacturing Microbial Control of Drug Substance Manufacturing – Equipment Design and use – Personnel – The Manufacturing Environment Th M f i E i August 4, 2014 IVT Microbiology Week 24 Content of the USP Chapter Content of the USP Chapter • Microbial Microbial Assessment of Non Assessment of Non‐sterile sterile Product Product Manufacturing Environment – Microbial Sampling – Microbial Identification – Active Measures for Microbial Control • Overall Overall Management of a Microbiological Control Management of a Microbiological Control Program • References August 4, 2014 IVT Microbiology Week 25 Presentation Outline Presentation Outline • The intention of the USP Microbiology Committee of Experts • Expected impact of the new USP chapter <1115> • Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug products • Content of the USP Chapter <1115> • Risk hierarchy by non‐sterile dosage form • Factors increasing microbial contamination risk • Drug substances Drug substances • Pharmaceutical excipients • Manufacturingg August 4, 2014 IVT Microbiology Week 26 Risk Hierarchy Risk Hierarchy Hierarchy of risk due to microbial contamination by route of administration (High to low): route of administration (High to low): • • • • • • • • • Metered‐dose and dry powder inhalants Nasal sprays p y Otics Vaginal suppositories Topicals Rectal suppositories Oral liquids (aqueous) Liquid‐filled capsules Compressed tablets and powder filled capsule Compressed tablets and powder‐filled capsule August 4, 2014 IVT Microbiology Week 27 Presentation Outline Presentation Outline • The intention of the USP Microbiology Committee of Experts • Expected impact of the new USP chapter <1115> • Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug products • Content of the USP Chapter <1115> • Risk hierarchy by dosage form • Other factors increasing microbial contamination risk • Drug substances Drug substances • Pharmaceutical excipients • Manufacturingg August 4, 2014 IVT Microbiology Week 28 Increased Microbial Risk Increased Microbial Risk • The development of novel drug delivery systems e g dry powder inhalants nasal sprays e.g., dry powder inhalants, nasal sprays, transdermal patches, and drug‐coated transplanted medical devices that may increase patient risk to microbial contamination due to ti t i k t i bi l t i ti d t their invasiveness within the human body. • The sourcing of drug substances from The sourcing of drug substances from manufacturing facilities in third‐ world countries with increased risk of potential product contamination due to poor GMPs contamination due to poor GMPs • Globalization with drugs manufactured outside the US and transported around the world. the US and transported around the world. August 4, 2014 IVT Microbiology Week 29 Increased Microbial Risk Increased Microbial Risk • The The growth of off growth of off‐label label dosage regimes and dosage regimes and patient populations as physicians seek wider clinical applications and change administration pp g practices. • The increased aggressiveness and invasiveness The increased aggressiveness and invasiveness of medical treatments. • Increases in patients who due to their age or Increases in patients who due to their age or medical condition are seriously immunologically compromised and are aggressively treated. p gg y August 4, 2014 IVT Microbiology Week 30 Presentation Outline Presentation Outline • The intention of the USP Microbiology Committee of Experts • Expected impact of the new USP chapter <1115> • Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug products • Content of the USP Chapter <1115> • Risk hierarchy by dosage form • Factors increasing microbial contamination risk • Drug substances Drug substances • Pharmaceutical excipients • Manufacturingg August 4, 2014 IVT Microbiology Week 31 Drug Substances Drug Substances • The bioburden of DS manufactured by y chemical synthesis will largely depend on the final synthetic, isolation and purification steps the drying process micronization for steps, the drying process, micronization for particle size reduction, and to a lesser extent the drug substance packaging. g p g g • In general, the chemical transformations and isolation of intermediates typically involve reactions using reagents, solvents, and i i l d elevated temperatures that are incompatible with the survival of microorganisms with the survival of microorganisms. August 4, 2014 IVT Microbiology Week 32 Chemical Synthesis Chemical Synthesis August 4, 2014 IVT Microbiology Week 33 Drug Substances Drug Substances • The The bioburden of the starting materials, bioburden of the starting materials reagents, and intermediates will have little or no impact on the bioburden of the drug no impact on the bioburden of the drug substances and may be discounted. • The bioburden of a plant‐ The bioburden of a plant or animal‐derived or animal derived drug substance will depend on the degree of processes of the material processes of the material. August 4, 2014 IVT Microbiology Week 34 Drug Substances Drug Substances • The impact of the final purification and isolation e pact o t e a pu cat o a d so at o steps on the DS bioburden depends on the solvent used in the mother liquor, temperature of the isolation process, the inclusion of a f h l h l f bioburden‐controlling filtration step, the material recovery method and drying process material recovery method, and drying process. • Typically 90% of the isolations employ organic solvent or a mixture of organic solvents and solvent or a mixture of organic solvents and water and not water, which reduces the likelihood of microbial contamination. August 4, 2014 IVT Microbiology Week 35 Drug Substances Drug Substances • The most common organic solvents used in g industrial organic syntheses include toluene, tetrahydrofuran, dichloromethane, ethyl acetate 2 propanol methanol denatured acetate, 2‐propanol, methanol, denatured alcohol, acetic acid, n‐heptane, and acetronitrile. All are inimical to the survival of microorganisms • If water is the primary solvent, purified water, USP is used for DS used in non‐sterile i df di il drug products and low‐endotoxin purified water in sterile drug products water in sterile drug products. August 4, 2014 IVT Microbiology Week 36 Product Development Points to be considered when assessing the potential microbial risk associated with non‐sterile d drug products: d t • • • • • • • • • • Synthesis, isolation and final purification of the drug substance Microbiological attributes of the drug substance Microbiological attributes of the drug substance Formulation and physicochemical attributes of the drug product Water activity of the drug product Manufacturing process Packaging and delivery system Storage conditions of the drug substance and product Storage conditions of the drug substance and product Route of administration Expected treatment procedure and dosage regimen Age and health condition of the intended recipients of the drug August 4, 2014 IVT Microbiology Week 37 U.S. Regulatory Documents U.S. Regulatory Documents • FDA FDA Good Manufacturing Practices found in 21 CFR Good Manufacturing Practices found in 21 CFR Part 211 • 211.42 Design and Construction • 211.46 Ventilation, Air Filtration. Air heating and Cooling • 211.56 Sanitation • 211.113 Control of Microbiological Contamination August 4, 2014 IVT Microbiology Week 38 Manufacturing Risk Factors Manufacturing Risk Factors Microbial risk factors in descending order: Microbial risk factors in descending order: • • • • • Ingredient water Pharmaceutical ingredients g Processing equipment Manufacturing personnel Manufacturing environment August 4, 2014 IVT Microbiology Week 39 Pharmaceutical Water Systems Pharmaceutical Water Systems August 4, 2014 IVT Microbiology Week 40 Classification of Pharmaceutical Excipients • • • • • Binders Disintegrants Fillers (diluents) Lubricants Glidants (flow enhancers) • Compression aids • Colors l • Sweeteners August 4, 2014 • • • • Caking agents Caking agents Buffers Preservatives Suspending/dispersing agents • Film formers/coatings • Flavors • Printing inks IVT Microbiology Week 41 Common Excipients used in Solid Dosage Forms Excipient Classification Common Excipients Diluent or Filler Lactose, Sucrose, Kaolin, Dibasic Calcium Phosphate, Calcium Sulfate, and Calcium Carbonate Binders Water, Alcohol Water Alcohol, Starch Paste Paste, Gelatin Solutions Solutions, Tragacanth, Sodium Alginate, Carboxymethyl Cellulose, Polyethylene Glycol and Povidone Lubricants Magnesium Stearate, Stearate Calcium Stearate, Stearate Talc Talc, Stearic Acid, Starch, Mineral Oil, Sodium Chloride, Sodium Benzoate, and Carbowax 4000 or 6000 Disintegrating Agents Corn Starch Starch, Methylcellulose Methylcellulose, Sodium Carboxymethyl Cellulose, Alginic Acid, Microcrystalline Cellulose and Gums g Sweetening Agents Mannitol,, Lactose,, Sorbitol,, Fructose,, Saccharine,, and Aspartame August 4, 2014 IVT Microbiology Week 42 Risk Analysis of Pharmaceutical Excipients Classification Examples of Excipients y Synthetic Material Povidone (polyvinyl pyrrolidone) and (p y y py ) Crospovidone (A homopolymer of cross‐ linked N‐vinyl‐2 pyrrolidone) Semi‐synthetic y Captisol (Chemically‐modified cylodextrin) p ( y y ) material and Hydroxypropyl Methylcellulose Microbial Risk Little or none Low to moderate Plant‐derived Corn Starch, Microcrystalline Cellulose, and Moderate Material Sucrose Animal‐ derived Material Lactose (Extractive), Magnesium Stearate (Processed chemically from tallow), and Gelatin (Purified from bone or hide) Gelatin (Purified from bone or hide) Moderate to high Mineral‐ derived Material Talc (Extractive) and Dibasic Calcium Phosphate (Processed chemically from a mineral calcium carbonate and phosphoric mineral calcium carbonate and phosphoric acid) Low to moderate August 4, 2014 IVT Microbiology Week 43 Talc Mining Talc Mining August 4, 2014 IVT Microbiology Week 44 Lactose Production Lactose Production • Whey protein concentrates are powder made by drying yp p y y g the retentate from the Ultra Filtration of whey. The concentration of whey proteins is primarily achieved by UF and Diafiltration UF and Diafiltration. • The permeate of UF membrane is high in lactose content, so that is used for manufacturing lactose powder. Permeate recovered is concentrated to d di d minimum 62% TS level in an evaporator and then cooled under controlled conditions for Lactose crystallization. Crystals are washed, decanted and spray dried to produce pharma grade lactose. August 4, 2014 IVT Microbiology Week 45 Lactose Manufacturing Lactose Manufacturing • Lactose spray dryer Lactose spray dryer August 4, 2014 IVT Microbiology Week 46 Risk Assessment Risk Assessment In Failure Mode and Effects Analysis (FMEA) terms y ( ) risk was defined in terms of occurrence (O), severity (S) and detection (D). The risk is expressed as O x S X D Using this tool risk is minimized if occurrences D. Using this tool, risk is minimized if occurrences decrease, severity of the effect of failure is decreased, and the efficiency of detection of a failure increases. Note: The less readily that microbial contamination can be detected the higher the value of D and the overall risk overall risk. For a discussion of risk analysis see ICH Q9 Quality Risk Management August 4, 2014 IVT Microbiology Week 47 Simple Risk Analysis Simple Risk Analysis An approach is to assign a score from 1 to 3 to pp g the following: • Severity (S) as a consequence of failure • Occurrence (O) as the likelihood of failure occurring based on past experience • Detection (D) as the likelihood that failure detection will take place with the proposed monitoring system • The risk is determined by the product of S x O x D D August 4, 2014 IVT Microbiology Week 48 Risk Analysis – Occurrences (O), Susceptibility (S) and Detectability (D) bl ( ) d bl ( ) Excipient p Manufacturing Process O S D OxSxD Synthetic Material 1 2 1 2 Semi-synthetic material 1 2 2 4 Plant-derived Material 2 3 2 12 Animal-derived Animal derived Material 3 3 2 18 Mineral-derived Material 2 2 2 8 August 4, 2014 IVT Microbiology Week 49 ICH Q6A ICH Q6A • For drug product release testing, ICH Q6A Test gp g, Q Procedures and Acceptance Criteria for New Drug Substances and Drug Products provides decision trees that guide manufacturers on necessary test trees that guide manufacturers on necessary test strategies based on the nature of the product. The establishment of microbiological attributes are • The establishment of microbiological attributes are described in Decision Tree 6 (Drug Substances) and Decision Tree 8 (Drug Products). • Low water activity is a highlighted attribute for reduced testing strategies. August 4, 2014 IVT Microbiology Week 50 Manufacturing Environment Common design elements to control microbial contamination: • Non‐porous walls, ceilings and floors that are readily cleanable • Floor drains that can be closed during processing or fitted with a air break if opened during area and equipment cleaning • Access should be limited to essential personnel • Material, equipment and personnel flows should avoid M t i l i t d l fl h ld id contamination • Ventilation and air filtration should be adequate to maintain q the specified cleanliness, space pressurization, temperature and humidity August 4, 2014 IVT Microbiology Week 51 Manufacturing Equipment Manufacturing Equipment For bioburden control equipment should have the For bioburden control equipment should have the following attributes: • Sanitary design y g • Readily cleaned preferably using a CIP system Self‐draining draining to eliminate stagnate water to eliminate stagnate water • Self • Preventative maintenance program to periodically replace valves, seals, filters and hosing p , , g • Inclusion of microbial monitoring in cleaning validation protocols p August 4, 2014 IVT Microbiology Week 52 Dosage Forms Dosage Forms Over 80% of the current drug products by the number of prescription are marketed as oral solid number of prescription are marketed as oral solid dosage forms, i.e. powder‐ and liquid‐ filled capsules and compressed tablets, which have a very low risk of microbial contamination because of their manufacturing processes, low water activity and route of administration route of administration. Many other non‐sterile drug products, e.g., oral liquids, topicals, nasal sprays, etc, may be q , p , p y, , y susceptible to microbial growth and have more critical routes of administration than an oral solid. August 4, 2014 IVT Microbiology Week 53 Risk Assessment Risk Assessment What other tools are available for this risk assessment? In the 1960's, the Pillsbury Company, the U.S. Army, and National Aeronautics and Space Administration (NASA) i t d d (NASA) introduced a system for assuring pathogen‐ t f i th free foods for the space program. This system, called Hazard Analysis and Critical This system, called Hazard Analysis and Critical Control Points (HACCP), is a focus on critical food safety areas as part of total quality programs and may be a tool applicable to the pharmaceutical industry be a tool applicable to the pharmaceutical industry. August 4, 2014 IVT Microbiology Week 54 HACCP • HACCP HACCP involves a critical examination of the involves a critical examination of the entire food manufacturing process to determine every step where there is a determine every step where there is a possibility of physical, chemical, or microbiological contamination of the food microbiological contamination of the food, which would render it unsafe or unacceptable for human consumption. These unacceptable for human consumption. These identified points are the critical control points (CCP). points (CCP). August 4, 2014 IVT Microbiology Week 55 HACCP There are seven principles to HACCP: There are seven principles to HACCP: 1. Analyze hazards, 2 determine CCPs 2. determine CCPs, 3. establish critical limits, 4 establish monitoring procedures 4. establish monitoring procedures, 5. establish deviation procedures, 6 establish verification procedures and 6. establish verification procedures, and 7. establish record keeping procedures August 4, 2014 IVT Microbiology Week 56 Tablet Manufacturing Tablet Manufacturing In general, the most critical processing steps with g , p g p respect to potential microbial contamination are the procurement of pharmaceutical ingredients, wet granulation and milling and tablet coating wet granulation and milling and tablet coating (Bolded red in list of manufacturing steps). For example, the holding time of aqueous film coating p g q g solutions may be a critical control point. In contrast, fluid bed drying and compression are potentially bioburden‐reduction steps (Bolded t ti ll bi b d d ti t (B ld d green) August 4, 2014 IVT Microbiology Week 57 Tablet Manufacturing Tablet Manufacturing For example, the processing steps for the manufacture of a film‐coated of a film coated compressed tablet are: compressed tablet are: Procurement of pharmaceutical ingredients Warehousing pharmaceutical ingredients Batching of the pharmaceutical ingredients Blending Wet granulation and milling l i d illi Drying Tablet compression Tablet compression Tablet coating Packaging g g Distribution August 4, 2014 IVT Microbiology Week 58 Tablet Manufacturing Tablet Manufacturing • Unit Unit processes involved in making tablets include processes involved in making tablets include particle size reduction and sizing (milling), blending, granulation, drying, compaction (compression), (frequently) coating and packaging. August 4, 2014 IVT Microbiology Week 59 Tablet Manufacturing Tablet Manufacturing August 4, 2014 IVT Microbiology Week 60 Risk Analysis for Tablet Manufacturing Risk Analysis for Tablet Manufacturing Manufacturing Step Contamination Preventative Potential Measures/Critical Control Points Remarks Wet granulation and milling Moderate Emphasis on water system validation and equipment cleaning to prevent microbial contamination. Water activity measurement may be used to evaluate the ability of the granulation to support microbial growth August 4, 2014 Equipment design. Cleaning validation. Monitor purified water used in granulation solutions for microbial counts (CCP). Holding Time (CCP). IVT Microbiology Week 61 Risk Analysis for Tablet Manufacturing Risk Analysis for Tablet Manufacturing Manufacturing Step Contamination Potential Preventative Measures/Critical Control Points Remarks Tablet Coating Moderate to High Equipment cleaning and solution holding time (CCP) Incoming microbial testing of ingredients (CCP) Monitor purified water used in coating solutions for microbial counts (CCP) Water-based coating solution will support microbial growth. Holding times need to be justified. August 4, 2014 IVT Microbiology Week 62 Risk Analysis Risk Analysis • After Anastasia Lois, 2013 After Anastasia Lois, 2013 August 4, 2014 IVT Microbiology Week 63 Conclusions The management of a successful microbiological g g control program includes the following: • Identification of suitable suppliers of pharmaceutical ingredients and excipients that have h l d d h h good microbiological quality • Conducting a microbial risk assessment of the drug Conducting a microbial risk assessment of the drug formulation, manufacturing process and packaging system and mitigating those risks • The establishment of an appropriate monitoring and control system. August 4, 2014 IVT Microbiology Week 64 Contact Information Contact Information • Tony Cundell, Consulting Microbiologist Tony Cundell, Consulting Microbiologist • Email address: [email protected] • Phone number: 01 914 725 Phone number: 01 914 725‐3947 3947 August 4, 2014 IVT Microbiology Week 65