SHANKAR GUPTA

Critical quality events-QP EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use - Annex 16: Certification by a Qualified Person and Batch Release Quality Event: The event occurred during manufacturing / analysis of batch / lot or event occurred during the batch / lot is in the distribution system or as a market feedback which is likely to have potential impact on finished product Qualified Person (QP): QP is the person responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force in the Member State where certification takes place, in accordance with the requirements of the marketing authorization (MA) and with Good Manufacturing Practice (GMP) Periodic Events Notification- Quality events summary report shall be prepared on quarterly basis 1.     Incidents- Incidents which have a systemic effect: · Any validation / qualificat...

Steam In Place - Steam In Place vs Sterilize In Place- Steam in place term used to describe in situ sterilization using steam. Sterilize in place term used to describe in situ sterilization using various types of gaseous or liquid sterilizing agents including steam. Terminal sterilization = Steam under pressure - A probability of no more than one no-Sterile unit in a million (10-6) is readily achievable. Aseptic - A controlled process or condition in which the level of microbial contamination is reduced to the degree that microorganisms can be excluded from a product during processing.

Air velocity measurement As part of risk assessment this evaluation should also consider the selection of locations for the critical control points for monitoring air velocity as well as viable and non-viable particles. 1. Problem Statement- Where should airflow velocity measurements be taken with respect to a filling line or other aseptic processing areas? Recommendation Airflow velocity measurements should be taken at locations where meaningful and reproducible results can be obtained. This is typically at a distance of 6 inches from the filter face . Rationale for Recommendation The primary reason for airflow velocity measurements in unidirectional airflow areas (e.g., areas where product, product contact packaging components, and product contact surfaces are exposed) is to assure there is adequate airflow to protect the materials from external airborne contamination . Accurate measurements can be taken and changes over time detected when airflow velocities are e...

USP general chapter - 797 1. Unidirectional airflow 2. Sweeping action over and away from the product under dynamic conditions. 3. It is useful in identifying eddy currents and recirculation of air flow as a means of assessing risk of contamination in critical areas within a clean room. First air should contact critical components or products before contacting anything else. It should be free of eddy currents or deviant air that can act as a channel or reservoir for contaminants. It is important to evaluate air flow patterns to assure that these patterns do not pose a risk of distributing particles from sources such as surrounding environment, personal, operations, materials or equipment. These tests are used to demonstrate that airflow under operational conditions doesn't contribute to contamination risk. Regulatory bodies requires documented air pattern analysis with written conclusions including the effects of the aseptic interventions in critical areas. Smoke s...

Bubble point: The measured differential gas pressure which a wetting liquid (e.g., water, alcohol, product) is pushed out of the largest pores of a wetted porous membrane and a steady stream of gas bubbles or bulk gas flow is detected. Bubble point test: A test to indicate the maximum pore size of a filter. The differential gas pressure at which a liquid (usually water) is pushed out of the largest pores and a steady stream of gas bubbles is detected from a previously wetted filter under specific test conditions. Used to test filter integrity with specific, validated, pressure values, wetting liquids and temperatures for specific pore-size (and type of) filters. Water intrusion test/ HydroCorr test : The HydroCorr test is based on the fact that water is repelled by the pores Hydrophobic filters by surface tension and capillary forces. The HydroCorr test is a highly sensitive, non-alcohol, water flow integrity test for hydrophobic membrane filters. The minimum pressure require...

Test organisms- 1. Candida albicans (ATCC No. 10231) 2. Aspergillus brasiliensis (ATCC No. 16404) (formerly Aspergillus niger) 3. Escherichia coli (ATCC No. 8739) 4. Pseudomonas aeruginosa (ATCC No. 9027) 5. Staphylococcus aureus (ATCC No. 6538)

1. Water and other raw materials - (Pseudomonas species) 2. Environmental- (Bacillus and moulds) 3. Damaged surfaces - (Bacillus and moulds)

Defects- a) Freezing stage- 1. Puffing - Top part of cake separate from lower part, sometimes rising to the shoulder of vial. This typically happens as a result of incomplete freezing prior to pulling a chamber vacuum for primary drying phase. It is important to allow adequate time for freezing (and temperature conditioning) before pulling chamber vacuum. b) Primary drying stage- 1. Meltback - Usually occurs as a result of eutectic melting of crystalline components of the formulation (eg- Glycine or mannitol). The frozen part of the plug melts and dissolves the dry portion of the plug, leaving (at its worst) a concentrated solution in the bottom of the vial. The problem is avoided by staying below Tg (and so below eutectic temperature of crystalline components). A similar product appearance will result if vacuum is lost before primary drying is complete, or if secondary drying is begun prematurely. 2. Collapse - Product affected by collapse is not just aestheticall...

GMP REGULATIONS- https://www.ecfr.gov/cgi-bin/text-idx?SID=3ee286332416f26a91d9e6d786a604ab&mc=true&tpl=/ecfrbrowse/Title21/21tab_02.tpl http://eng.sfda.gov.cn/WS03/CL0768/ https://ec.europa.eu/health/documents/eudralex/vol-4/ http://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/index.html https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm121568.htm http://www.medsafe.govt.nz/consultations/current.asp https://www.tga.gov.au/open-consultations-reviews GUIDELINES AND STANDARDS- https://www.ispe.org/initiatives/regulatory-resources/gmp/regulatory-guidelines http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en/ https://extranet.who.int/prequal/ http://digicollection.org/whoqapharm/cl/CL3.1.1/#hlCL3_1_1 http://www.ich.org/products/guidelines.html https://picscheme.org/en/publications http://www.fao.org/fao-who-codexalimentarius/standards/list-standards/en/ http://www.sidiwor...

1. Bacillocid 2% V/V a) 1, 6 Dihydroxy 2, 5- Dioxahexane (Chemically bound formeldehyde) b) Glutaraldehyde c) Benzalkonium chloride d) Alkyl urea derivatives 2. Minncare 20% V/V a) Hydrogen peroxide b) Per-acetic acid c) Acetic acid 3. Virosil 5% V/V/ 20% V/V a) Hydrogen peroxide 10% W/V b) Diluted Silver Nitrate solution 0.01% W/V 4. Novacide 1% V/V a) Poly (Hexa methylene biguanide) Hydrochloride 3% W/ V b) Didecyle dimethyl ammonium chloride 10% W/V

Cause: Aggregation of molecules in liquid media- Limit- 1. SVP a) up to 10 micron= maximum 6000/ Container b) up to 25 micron= maximum 600/ Container 2. LVP a) up to 10 micron= maximum 25/ mL b) up to 25 micron= maximum 3/ mL

FDA 2004 Guidance for Industry EU Annex 1 USP <1072> ISO 13408-1 and 14698 USP general information chapter <1116> “Microbial Evaluation and Classification of Clean Rooms and Other Controlled Environments” PDA- 13 (Fundamentals of an Environmental Monitoring Program) Colony Forming Unit (CFU): A single macroscopic colony formed after the introduction of one (or more) microorganism(s) to a microbiological growth medium. Continuous Monitoring: A process of data collection where conditions are monitored continuously throughout the operation. In most U.S. applications, this definition implies “during production.” For ISO applications, this means twenty-four hours per day, seven days a week. Frequent Monitoring: A process of collecting data where conditions are monitored at least once per hour. In most U.S. applications, this means during production. In most ISO applications this means twenty-four hours per day, seven days per week. Disinfection: The ch...

Anaerobic bacteria are organisms that are capable of surviving and growing in an atmosphere of little or no oxygen. Anaerobic bacteria can be further broken down based on their relationship to oxygen: obligate, aerotolerant or facultative anaerobe. They can be found in a variety of environments ranging from soil and water to the bodies of humans and other animals. Many anaerobic bacteria are found normally in the human body; in fact, in the intestines of humans, anaerobic bacteria outnumber aerobic bacteria 1,000 to 1.

NVPC Online NVPC: Make= Beckman; Model= Met one 6015P; Capacity= 1CFM SOFTWARE= EnVigil Critical alarm: Critical alarms are those alarms when generated indicate excursion which may impact the product quality. Alarm generated in location where the NVPC probe is in close proximity to the product/ sterile container closure/ product contact path. Location for critical alarms includes grade A location - Filling station, Bunging station, Bunging Hopper station, Portable cart, IOS station, AGV station, Near lyophilizer door open, between lyophilizers (near Lyo) and Lyo LAF (rigid barrier transfer conveyor). Critical alarms include the following- 1.     Particle count excursion beyond the acceptance criteria at a particular location. 2.     Sensor Failure, Counter Flow Failure, ERROR or SKIPPED message. Ensure and verify the status of counter flow to meet the below set limit- Target Counter flow – 1.0 CFM. Minimum counter flow: ...

Master Formula Record (MFR) for a new product from Formulation Development or Technical Services- Bill of Material (BOM): A list of actives, excipients, and primary packing materials used to manufacture a particular product along with the Batch size, quantity required for the batch and MOC of Consumables. Process Instruction: A list of ingredients used to manufacture a dosage form along with the manufacturing procedure, hold time recommendation and schematic representation. CREATION OF MASTER FORMULA RECORD The Master Formula Record shall consist of two parts- §   Part One: Bill of Materials (BOM) §   Part Two: Process Instruction (PI) Ø   MFR= BOM + PI BOM consists of Finished Product Information, Bill of Materials, Potency calculation with molecular weight details, Raw material & Primary Packing material information and Stock solution preparation and Process Aids (Materials of Construction (MOC) of Filters & Tubing’s without item ...

PDA Technical report No. : 3 (Revised 2013) Dry heat process used for sterilization and depyrogenation. Bacterial Endotoxin Test (BET) - Assay for measuring active endotoxins by combining a liquid test sample with LAL (Limulus Amoebocyte Lysate) reagent and measuring the resulting proportional reaction via visual, turbidimetric, chromogenic, or other validated means of detection. BI Challenge system - A test system containing viable microorganisms of pure and specified strain providing a defined resistance to a specified sterilization process. Depyrogenation - Destruction and /or removal of bacterial endotoxins. It demonstrates at least 99.9 % or 3 Log endotoxins reduction. D- Value- Time in minutes required for a one-logarithm or 90% reduction of microorganisms used as biological indicator under specified lethal conditions. Dwell Time- Period that items are subjected to a given processing conditions. Endotoxin Indicator (EI) for depyrogenation - Vial of endotoxin (or ...