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Group Names: October 15, 2015 Professor Name: Amoxicillin Manufacturing and Production CHE 714 Table of Contents 2 Introduction Type of Dosage Forms Active Pharmaceutical Ingredient and Excipients Good Manufacturing Practice Batch Production Manufacturing Process Standards & Validation Quality Control Analytical & Stability Testing Packaging Conclusion What is Amoxicillin ?-lactam antibiotic Derived from penicillin Effective against wide range of infections Both gram positive and negative Can be orally administered 3 Amoxicillin History Developed in 1972 by "The Beecham Group plc" (Now GlaxoSmithKline) 1981: amoxicillin clavulanate potassium tablets patented 1998: sold under trade names amoxicillin, amoxil, and trimox On World Health Organization's list of Essential Medicines One of most commonly prescribed antibiotics to children Costs about $16 USD for 10 days worth 4 Dosage Forms Categories of Dosage Form: 1. Tablets (200mg-875mg) 2. Chewable tablets (125-500 mg) 3. Dispersible tablets (750 mg) 5 Dosage Forms 4. Capsules (250mg-875mg) 5. Oral suspension /drops (50mg/ml?400 mg/ml) 6. Injection (250mg?1000mg) 6 Amoxicillin Sample Label 7 Figure 1: Amoxicillin label (Medical Library, 2014) Active Pharmaceutical Ingredient Amoxicillin trihydrate highly active against a broad spectrum of bacteria high solubility, high absorption rate, highly stable under acid conditions produced by a semisynthetic route crystallization determines solid state properties and impurities present in powder 8 Active Pharmaceutical Ingredient Method of Preparing: Dane Salt Method (1979, US 4231954) Agglomerates of beta-lactam antibiotics (2003, EP1283034) 9 Good Manufacturing Practices (GMP) GMPs are guidelines which provide minimum requirements that a pharmaceutical manufacturer must follow and meet to ensure that the drugs are safe, high quality and do not pose any risk to the consumer or public. It covers all aspects of production from the starting raw materials, premises, packaging and equipment to the training and personal hygiene of staff. 10 Figure 1: GMP Overview (Daghlas Fadi, 2014) Figure 2: GMP Overview (Daghlas Fadi, 2014) Batch Production Records Provide documents every time manufacture a batch of a regulate supplement Include complete information relating to the production and control of each batch such as batch number, Date, Critical Process Parameters, Identity of equipment and processing lines used in producing the batch, ingredient measurement and step by step instructions Description for Packaging and labeling procedures. 11 Excipients Substance added alongside active ingredient to aid: Absorption Stability Manufacturing Tablets and Capsules Absorption Disintegrant: Silica Colloidal Anhydrous Stability Clavulanic Acid added to inhibit ?-lactamase Manufacturing Glidant: colloidal silicon dioxide (0.5 % w/w) Lubricant: magnesium stearate (0.5 % w/w) Suspensions Stability Clavulanic Acid added to inhibit ?-lactamase Preservative: Sodium citrate anhydrous Trisodium citrate Manufacturing Glidant: Talc Filler: Silicon dioxide 12 Manufacturing Processes of Amoxicillin Tablet manufacturing processes Capsule manufacturing processes 13 Tablet Manufacturing Process Since Amoxicillin comes in Solid and liquid forms, there are 3 principal methods of developing Amoxicillin: Direct Compression Dry Granulation Wet Granulation Figure 3: Unit Operation (Pharma Tips, 2010) 14 Tablet Manufacturing Process Table 1: Comparison between the Tablets Manufacturing Process (Niazi, 2010) 15 Direct Compression Manufacturing Process used when ingredients can be blended and placed in a tablet press 16 {E87B9F97-8C42-4081-91DA-907A86238EA9}Advantages Limitations Cost effectiveness Segregation Stability Cost Faster dissolution Low dilution potential Less wears and tears punches Re-workability Simplified validation Lubricant Sensitivity Variation in functionality Dry Granulation Manufacturing Process Used for Granulate materials which are sensitive to heat and/or moisture Formed Through Pressure The powder mixture is compressed without the use of heat and solvent Two methods are used for dry granulation; slugging and chilosonator or Roller compaction Figure 4: Block Diagram for Dry Granulation (Niazi, 2010) 17 Dry Granulation Manufacturing Process Table 2: Dry Granulation advantage and disadvantage ( Pharma Tips, 2010) {E87B9F97-8C42-4081-91DA-907A86238EA9}Advantage Disadvantage uses less equipments and space It requires a specialized heavy duty tablet press to form slug Eliminate heavy mixing equipment, costly and time consuming drying step required for wet granulation. It does not permit uniform colour distribution as can be Improve flow properties and bulk density Achieved with wet granulation where the dye can be incorporated into binder liquid Produce uniform blends The process tends to create more dust than wet granulation, increasing the potential contamination 18 Wet Granulation Manufacturing Process The most widely used process of agglomeration in pharmaceutical industry is wet granulation. Wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying. Important steps involved in the wet granulation: i)Mixing of the drug(s) and excipients ii)Preparation of binder solution iii)Mixing of binder solution with powder mixture to form wet mass. iv)Drying of moist granules v)Mixing of screened granules with disintegrant, glidant, and lubricant. 19 Wet Granulation Manufacturing Process 20 {E87B9F97-8C42-4081-91DA-907A86238EA9}Advantages permits mechanical handling of powders without loss of mix quality: improves the flow of powders by increasing particle size and sphericity increases and improves the uniformity of powder density improves cohesion during and after compaction reduces air entrapment: reduces the level of dust and cross-contamination allows for the addition of a liquid phase to powders (wet process only): Makes hydrophobic surfaces hydrophilic. Wet Granulation Manufacturing Process 21 {E87B9F97-8C42-4081-91DA-907A86238EA9}Limitation The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements. Loss of material during various stages of processing Stability may be major concern for moisture sensitive or thermo labile drugs Multiple processing steps add complexity and make validation and control difficult An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated. Capsule Manufacturing Process Encapsulation is the only method in the capsule manufacturing process it is a process in which tiny particles or droplets are surrounded by a coating to give small capsules of many useful properties. Steps of the encapsulation (Solid Dosage Expert Techceuticals. 2015): The capsule filler must first position all of the incoming capsules into an upright position (rectification) separate the cap from the body attain the proper fill volume the product filled body is rejoined with the cap and ejected from the machine 22 Types of encapsulation Hand operated: The Hand Operated capsule filler requires the operator to do all steps:rectify, fill, tamp, close and eject Semi-automatic: requires the operator to move rings (capsule holder rings) from the rectifier to the filling and closing stations up to 25,000 capsule/hour Automatic: divided into two categories: Continuous and Intermittent operation. The machine is divided into segments. Each segment indexes from each machine function. up to 90,000 capsule/hour Common Capsule defects include: Dented, cracked, split, oversized caps, and empty capsules after the filling cycle. 23 Standards for Manufacturing ISO certifications: ISO 9001: customer service oriented certification ISO 17025: quality tests oriented certification ISO Guide 34: accreditation dealing directly with Certified Reference Material Manufacturers 24 Standards for Manufacturing Manufacturers produce standards: specific functions: reference standard, performance verification, residue analysis, etc specific Pharmacopeia Standards: British, French, US, Swiss, European, WHO Certificate of Analysis: product info, toxicological data, analytical data, physical data, expiry date, storage info, signature Primary Reference: from manufacturers with ISO Guide 34 certification LGC Standards (UK, US, Germany), Sigma-Aldrich (115 countries) Secondary Reference: ISO 9001 25 Samples of Certificate of Analysis 26 Validation The concept of validation was first proposed by the Food and Drug Administration (FDA) in the mid 1970’s in order to improve the quality of pharmaceuticals. It confirms that the manufacturing processes have been properly developed and are under control. Establish documented evidence from the process design stage through commercial production. Provide documentary evidence that the process with their specified parameters. 27 Validation Figure 2: Process Validation Stages ( Kumar Abhilash and Navneet Upadhay, 2015) Types of Validation Prospective validation Retrospective validation Concurrent validation Revalidation Validation 29 Cleaning Validation is a process of removing contaminants from production equipment to ensure that the equipment are safe for product manufacturing. There are two general types of sampling: Direct Surface Sampling Rinse Samples Figure 5: Swap for Cleaning (The Texwipe Company LLC., n.d.) Cleaning Validation 30 Equipment / General Control 31 Equipment / General Control 32 Equipment / General Control 33 Equipment/General Control Environmental Condition of Manufacturing Area Observation Report 34 Control of Drug Product Specification for the drug product are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory agencies as conditions of drug approval. The following tests are applied to all drug products: Description: A qualitative statement regarding the appearance of the amoxicillin Identification Testing: HPLC, LC Assay: HPLC is commonly used for this testing Impurities: HPLC and LC are used for detecting amoxicillin impurities 35 Quality Control Impurity profile Authentication Certificate Stability Monitoring Program 36 Impurity of Amoxicillin In pharmaceutical it is crucial to analyze for impurity due to their potential for toxic effects on humans. Thus, the final product meets strict purity requirements. The guidelines recommended by ICH state that the acceptable levels for a known and unknown impurity in an amoxicillin API should be less than 0.15 and 0.10%, respectively. Amoxicillin impurity analysis is usually done using Agilent 1220 infinity Liquid Chromatography system. Impurities down to a level of 0.01% could be detected. 37 Impurity of Amoxicillin Amoxicillin can degrade to several different by-product: Figure 6: Amoxicillin degradation and impurities 38 Authentic certificate It is issued by the Quality Control with each batch of API released Issued Must list the following: The tests performed Customer requirements Numerical results Acceptance limits 39 Analytical Testing Acceptable Criteria 40 Analytical Testing 41 Stability Testing Amoxicillin Oral Suspension Stored Temperature: 27-29?C Amoxicillin stored in submerged water show slower degradation Found stable for 5 days under simulated home condition Lowest level of degradation when stored between 2?C and 8?C for 7 days 42 Stability Testing Amoxicillin Tablets Accelerated Stability Data 43 Stability Testing Amoxicillin Tablet Long term stability data 44 Packaging 45 Two different types of Packaging: Primary Secondary Glass Bottle Plastic Bottle Tablets in a blister pack in folding carton 46 Any Questions? 47 References Daghlas, Fadi. "GMP "Good Manufacturing Practice"" 26 Dec. 2014. Web. 12 Oct. 2015. <https://www.linkedin.com/pulse/gmp-good-manufacturing-practice-fadi-daghlas "Other References." Education. Compressed Air & Gas Institute. Web. 12 Oct. 2015. <http://www.cagi.org/education/other-references.aspx>. Kumar, Abhilash, and Navneet Upadhay. "PROCESS VALIDATION: A CRITICAL TOOL IN QUALITY ASSURANCE | PharmaTutor." Pharmatutor. 2015. Web. 12 Oct. 2015. <http://www.pharmatutor.org/articles/process-validation-critical-tool-in-quality-assurance Preet, S., Rao, R., & Nandu, S. (2011). Amoxicillin: A Broad Spectrum Antibiotic. International Journal of Pharmacy and Pharmaceutical Sciences, 3(3), 30-37. Retrieved September 22, 2015, from http://www.ijppsjournal.com/Vol3Issue3/2249.pdf Amoxicillin (Amoxil). (2008, March 31). Retrieved September 23, 2015, from http://www.emedexpert.com/facts/amoxicillin-facts.shtml Jerzsele, Á, & Nagy, G. (2009). The stability of amoxicillin trihydrate and potassium clavulanate combination in aqueous solutions. Acta Veterinaria Hungarica, 57(4), 485-493. http://dx.doi.org/10.1556/AVet.57.2009.4.3 48 References 9. "Swabs for Cleaning Validation." Pharmaceutical. The Texwipe Company LLC. Web. 13 Oct. 2015. <http://www.pharmaceuticalonline.com/doc/swabs-for-cleaning-validation-0001> 10. "Amoxicillin (NorthStar Rx LLC): FDA Package Insert, Page 5." MedLibrary.org. 2014. Web. 13 Oct. 2015. <http://medlibrary.org/lib/rx/meds/amoxicillin-44/page/5/>. 11. "Tablet Amoxicillin - Google Search." Tablet Amoxicillin - Google Search. Web. 13 Oct. 2015. <https://www.google.ca/search?q=tabletamoxicillin&espv=2&biw=1920&bih=979&site=webhp&source=lnms&tbm=isch&sa=X&sqi=2&ved=0CAYQ_AUoAWoVChMIqc776JO5yAIVC5QeCh2hTAMf#imgrc=w5lwCQycTgzwAM:>. 12. "Tablet Manufacturing Process." Pharma Tips. 6 July 2010. Web. 15 Oct. 2015. <http://pharmatips.doyouknow.in/Articles/Tablet-Manufacturing-Process.aspx>. 13. 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