MOST FREQUENTLY ASKED QUESTIONS Page 1 of 1 1 What is the definition of SOP? SOPs are detailed written instructions for the operations routinely performed in the course of any activities associated wi[.]
MOST FREQUENTLY ASKED QUESTIONS What is the definition of SOP? SOPs are detailed written instructions for the operations routinely performed in the course of any activities associated with pharmaceutical manufacturing Or A written authorized procedure which gives instructions for performing operations not necessarily specific to a given product / material, but of a more general nature the equipments preventive maintenance and cleaning; recall of products; purchasing; cleaning of premises and environmental control; sampling and inspection etc Or These are guidelines which describe how the activity is to be performed To achieve uniformity of results by each individual, it is mandatory to follow these guidelines SOP is like a “TELL and SHOW” concept Tell – means to establish and teach how the activity is to be carried out Show – means to provide the documented proof for the activity carried out What are the contents of the SOP? Objective/Purpose, Scope, Responsibility, Accountability, Procedure, List of formats/Annexure, Abbreviations, Reference, Revision History Which information should master document carry on every page not just one of the pages to meet GMP? Page number, document reference number and authorizing signatures How many SOPs required for equipment and what are those? Operation, Cleaning, Preventive maintenance/ Calibration, Sampling procedure What is the Batch production and control record (BPCR)? BPCR are prepared for each intermediate and API and include the complete information relating to the completion of each significant step in the Batch production What is the Master production & control record (MPCR)? To ensure the uniformity from batch to batch, master production instructions for each intermediate and API are prepared, dated and signed by one person, immediately checked, dated and signed by a person in the quality unit What are the content of the MPCR? The name of the intermediate or API being manufactured and an identifying document Page of MOST FREQUENTLY ASKED QUESTIONS reference code, if applicable A complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure Where the quantity is not fixed, the calculation for each batch size or rate of production should be included Variations to quantities should be included where they are justified The production location and major production equipment to be used Detailed production instructions, including the: - Sequences to be followed - ranges of process parameters to be used - sampling instructions and in-process controls with their acceptance criteria, where appropriate - time limits for completion of individual processing steps and/or the total process, where appropriate - expected yield ranges at appropriate phases of processing or time -Where appropriate, special notations and precautions to be followed, or crossreferences to these The instructions for storage of the intermediate or API to ensure its suitability for use, including the labeling and packaging materials and special storage conditions with time limits, where appropriate What is the list SOPs required in QA department? SOP for SOP, SOP for format preparation, change control, deviation, Non-conformance products, market complaints, product recall, returned goods, vendor qualification, preparation of BPCR & MPCR, Assigning of Mfg date & Expiry date, annual product review, corrective action & preventive action, process validation, cleaning validation, equipment qualification, glossary of terms, document control, Review of BPCR & analytical test report, batch numbering system, labeling practice, personnel training, BPCR issue and retrieval, batch release, self inspection (internal audit), file numbering system, preparation of organo-gram, preparation of COA, specimen signatures, Reprocess & rework of intermediates / API, Job responsibilities, Technology transfer, measurable quality objectives etc Page of MOST FREQUENTLY ASKED QUESTIONS What is the difference between intermediate and drug substance (API)? Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purifications before it become an API (Reference: ICH Q7A) API: Any substance or mixture of substances intended to be used in the manufacturing of a drug (medicinal) product and that when used in the production of a drug, becomes an API of the drug product Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure & function of the body (Reference: ICH Q7A) 10 What is the difference between drug substance and drug product? Drug substance (API): Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body (Reference: ICH Q7A) Drug product: The dosage form in the final immediate packaging intended for marketing (Reference: ICH Q7A) 11 What is the clean room? Clean rooms are defined as especially constructed, environmentally controlled enclosed spaces with respect to airborne particulates, temperature, humidity, air pressure, air flow patterns, air motion, vibration, noise, viable (living organisms) and lighting Particulate control includes: 12 Particulate & microbial contamination Particulate concentration & dispersion What are the classifications of clean rooms? Generally clean rooms are classified in to the following types as per different guidelines: Schedule M: Grade A, Grade B, Grade C, Grade D USFDA (US 209E): Class 1, Class 10, Class 100, Class 1000, Class 10000, Class 100,000 WHO 2002: Grade A, Grade B, Grade C, Grade D EU GMP: Grade A, Grade B, Grade C, Grade D ISO 14644-1: ISO-3, ISO-4, ISO-5, ISO-6, ISO-7, ISO-8, ISO-9 Britian (BS 5295): Class C, Class D, Class E or F, Class G or H, Class J, Class K Page of MOST FREQUENTLY ASKED QUESTIONS Australia (AS 1386): 0.035, 0.35, 3.5, 35, 350, 3500 Germany (VDI 2083): 1, 2, 3, 4, 5, 13 What is the difference between GMP & cGMP? GMP: GMP is the part of Quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production Such risks are essentially of two types: Cross-contamination (in particular of unexpected contamination) Mix-ups (confusion) cGMP: Current Good Manufacturing Practices This means any procedure / system adopted by the manufacturer which proves to be necessary and important for identity, strength and purity of a product 14 What is the difference between Qualification and Validation? Qualification is equipment / instrument oriented but validation is process oriented 15 What is the definition of Validation? Validation is the documented program that provides a high degree of assurance that a specific process, method or system will consistently produce a result meeting predetermined acceptance criteria 16 What is the definition of Qualification? Qualification is the action of proving and documenting that any equipment or ancillary systems are properly installed, work correctly, actually leads the expected results Qualification is part of validation, but the individual qualification steps alone not constitute process validation 17 What are the types of validation? Process validation, Analytical method validation, cleaning validation, facility validation, Utility validation & software validation 18 Definition of process validation and types of process validation? Process validation is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate / API meeting Page of MOST FREQUENTLY ASKED QUESTIONS its pre-determined specifications and quality attributes Process validation is three types: Prospective process validation Concurrent process validation Retrospective process validation 19 What is the prospective, concurrent and retrospective validation? Prospective process validation: Prospective Process validation shall be carried out for all the intermediate stages and Active Pharmaceutical Ingredients prior to the distribution of a new product [ICH: GMP, EU: GMP, PIC/S: GMP] Concurrent process validation: Any validated process undergoes a change either for the equipment or addition, deletion of a critical manufacturing process step, scale up or scale down, the same needs to be validated concurrently The validation is carried out only after a change of an existing validated process to support the change made or involve with the requirements Or A subset of prospective validation in which API batches are released for distribution, based on extensive testing, before completion of process validation Once data from additional batches produced under replicated conditions show uniformity, the process may be considered validated Or Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified [ICH: GMP, EU: GMP, PIC/S: GMP] Retrospective process validation: Validation of a process for a product already in distribution based upon accumulated production, testing and control data [ICH: GMP, EU: GMP, PIC/S: GMP] 20 What you mean by validation protocol and its contents of process validation? A written plan stating, how validation will be conducted and defining acceptance criteria Page of MOST FREQUENTLY ASKED QUESTIONS e.g: The protocol for manufacturing process identifies process equipments, critical process parameters, and / or operating range, product characteristics, sampling, test data to be collected, number of validations runs and acceptance test results Contents: 21 Protocol Approval Table of contents Objective Scope Responsibility Accountability Validation team Brief manufacturing process (Description, Flow chart, Reaction scheme) Selection of batches List of equipments used in the manufacturing process List of raw materials used in the manufacturing process Critical operations with justification In-process controls with acceptance criteria Sampling & testing plan with frequency Stability programm Data to be complied Acceptance criteria Intermediate & final products quality & yield Stability specification Document review Conclusion Revalidation criteria What is the definition of the procedure? A documented description of the operation to be performed, the precautions to be taken, and measures to be applied directly or indirectly related to the manufacture of an intermediate / API (Reference: ICH Q7A) Page of MOST FREQUENTLY ASKED QUESTIONS 22 What is the master document? Master document is a formally authorized source document relating to specifications, and / or manufacturing / analytical methods, which is protected from un-authorized access or amendment Documents required describing the quality system requirements in the organization Documents required describing the process or product characteristics Documents required by various regulatory agencies as part of compliance to GMP requirements Documents required for legal/ regulatory supports of the organization to meet the local regulations 23 Any other documents required by government / regulatory agency What is documentation? All the written production procedures, instructions and records, quality control procedures and recorded test results involved in the manufacturing of a medicinal product 24 What is the Technology Transfer? In the pharmaceutical industry, “technology transfer” refers to the processes that are needed for successful progress from drug discovery to product development to clinical trials to fullscale commercialization or it is the process by which a developer of technology makes its technology available to commercial partner that will exploit the technology To assure the drug quality, it is desire to make sure W’s and H, that is what1, when2, and why3 information should be transferred to where4 and by whom5 and how to transfer, then share knowledge and information of the technology transfer each other between stake holders related to drug manufacturing 25 What are the names of different countries of GMP guidelines for manufacturing of API? WHO GMP - Geneva ICH Q7A – Europe, Japan & US EU GMP - Europe MCC – South Africa APIC GMP – Active Pharmaceutical Ingredient Committee (A sector group of CEFIC) Page of MOST FREQUENTLY ASKED QUESTIONS USFDA GMP – United States of America PIC/S GMP- Germany Schedule M – Indian 26 What is preventive maintenance? It is periodic inspection and minor repairs of equipment as per schedule given in the SOP This enables smooth operation and long life of the equipment It also avoids major breakdown of the equipment during manufacturing of the product There are two types of maintenance Preventive maintenance: Schedule maintenance before any break down of machinery which prevents the machine break down Breakdown maintenance: Maintenance was done after stopping machine breakdown Weekly, Monthly, Quarterly, Half yearly and Yearly preventive maintenance 27 What you mean by “Quality Assurance”? The sum total of the organized arrangements made with the objects of ensuring that all APIs are of the quality required for their intended use and the quality systems are maintained 28 What are the types of different training programs? Induction training Job oriented training cGMP training On-going training 29 What is cGMP? Current Good Manufacturing Practices This means any procedure / system adopted by the manufacturer which proves to be necessary and important for identity, strength and purity of a product 30 What are the requirements for the equipment used in the manufacturing of process of API? Material of construction used for equipment should not React with component Get corroded, cause rusting Impart any impurities, absord Page of MOST FREQUENTLY ASKED QUESTIONS 31 Should be of appropriate design, adequate size and have smooth surface How are cGMP implemented? Training, compliance to SOPs, control on operations, following procedures / systems, monitoring through compliance audits 32 What is solvent? An organic or inorganic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacturing of an intermediate / API 33 What are the classifications of residual solvents? Residual solvents are classified into three class based on the possible risk to human health: Class-I (Solvents to be avoided) Class-II (Solvents to be limited) Class-III (Solvents with low toxic potential) 34 What is the difference between Responsibility and Accountability? Responsibility: Personnel directly associated with the implementation of the procedure Accountability: Person directly associated with the implementation of the system under which the procedure falls 35 Write the names of the different countries regulatory body (Like for India, USA, UK, Australia, South Africa, Brazil, Hungary, Germany, Philippines etc.) India – Schedule M United Status of America – USFDA (United state Food and Drug Administration) Australia – TGA (Therapeutic Goods Administration) United Kingdom – MHRA (Medicines & Health care products Regulatory Agency) South Africa – MCC (Medicine Control Council) Brazil – ANVISA (Brazilian Health Surveillance Agency or National Sanitary Surveillance Agency) Hungary - PIC/S (Pharmaceutical Inspection Convention or Pharmaceutical Inspection Cooperation Scheme) Germany – NIP (National Institute of Pharmacy) Philippines – BFAD (Beaureu of Food & Drug) 36 What is the abbreviation of MSDS and how many contents are mentioned & what are those? MSDS means Material Safety Data Sheet and it contains 16 contents Those are given below: Product Identification Page of MOST FREQUENTLY ASKED QUESTIONS Composition / Information on Ingredients Hazards identification First Aid measures Fire fighting measures Accidental release measures Handling & storage Exposure controls / Personal protection Physical & Chemical properties 10 Stability & Reactivity 11 Toxicological information 12 Ecological information 13 Disposal consideration 14 Transport information 15 Regulatory information 16 Other information 37 What is the static electricity? Denoting / pertaining to electricity which is at rest The electricity which is present on surface of a non-conductive body, where it is trapped from escaping, is called static electricity 38 What is the different types of Qualifications and write its flow? Qualifications are as follows: Design Qualification, Installation Qualification, Operational Qualification, and Performance Qualification URS/DS -FAT -SAT -DQ -IQ -OQ -PQ 39 What is audit/inspection and Why quality audit? Write different types of audits/inspection? A planned and systematic examination and check of a system, procedure or operation in order to monitor compliance with and the effectiveness of established standards and to allow for improvement and corrective measures where required Quality audit because of: To assess the effectiveness of the quality management system Assessing conformance Page 10 of 10 MOST FREQUENTLY ASKED QUESTIONS Records A Reprocessing by Repeating a F Production Record Review Chemical Reaction G Laboratory Records B Reprocessing by Physical H Distribution Records Manipulations I Complaint Files C Reworking of APIs and J Returned APIs and Intermediates Intermediates K API and Intermediate Salvaging XI Validation A Process Validation Strategy XII XIII XIV Control of Chemical, Biological, and Physical Contaminants XV APIs for Clinical Trials B The Validation Protocol A Quality Assurance Measures C Prospective Validation B Quality Control Unit D Concurrent Validation C Equipment and Facilities E Retrospective Validation D Control of Raw Materials Change Control/Revalidation E Production and Process Controls A Change-Control System F Process Validation B Change-Control Classification G Change Documentation Reprocessing/Reworking of APIs H Laboratory Controls and Intermediates I Documentation 190 What are the contents of South Africa (MCC) GMP Guidelines? Chapter 1: Quality Management Principles Quality Assurance Good Manufacturing Practice Quality Control Audits Quality Evaluation Audits Critical Procedures Chapter 2: Organisation and Personnel Principles Responsibilities of Key Personnel Legal Aspects Qualifications Training Hygiene Chapter 3: Premises and Equipment Principles Premises Page 57 of 57 MOST FREQUENTLY ASKED QUESTIONS Equipment Chapter 4: Materials Management Principles Purchasing Receiving Storage Issuing Chapter 5: Manufacturing Principle Validation Dispensing Manufacturing Operations In-process Control Contamination Reprocessing Packaging Principles Component Issue Packaging Operations In-process Control Contamination Finished Product Release Quality Control Principles Responsibilities Equipment Personnel Sampling Testing Standards, reagents Documentation Stability Chapter 6: Chapter 7: Chapter 8: Documentation Principles Preparation, Issue and Use of Documents Master Specifications Master Manufacturing Instructions Master Packaging Instructions Batch Records (Starting Materials) Batch Records (Packaging Materials) Page 58 of 58 MOST FREQUENTLY ASKED QUESTIONS Chapter 9: Batch Records (Manufacturing) Batch Records (Packaging) Other Procedures and Records Analytical Records Other Documentation Required Validation Principles Validation Master Plan Validation Protocol Validation Report Qualification Process Validation Analytical Method Validation Cleaning Validation Computer System Validation Validation of specific dosage forms Chapter 10: Returned Goods Principle Procedures Chapter 11: Complaints, Adverse Events, Recalls & Withdrawals Principles Complaints Adverse Events Recalls Chapter 12: Contract Manufacture, Analysis and Servicing Principles Manufacture And/Or Packaging Contract Analysis Service Contracts Chapter 13: Veterinary Medicines Principles General Requirements Special Requirement Chapter 14: Radio pharmaceuticals Principles Registration Requirements Personnel Premises and Equipment Production and Handling of Radioactive Preparations Page 59 of 59 MOST FREQUENTLY ASKED QUESTIONS Quality Control Packaging of Radio pharmaceuticals Non-radioactive Kits Distribution and Recalls Chapter 15: Biological Medicines Principles Personnel Premises and Equipment Animal Quarters and Care Documentation The Possibility of Contamination The Possibility of Infection Where the Product Itself is an Infectious Agent Starting Materials Seed Lot and Cell Bank System Operating Principles Quality Control Special Requirements for Final Testing Waste Disposal Chapter 16: Homeopathic Medicines Principles Premises Documentation Chapter 17: Medical Gases Principle General Requirements Pipelines Filling Areas Preparation of Returned Cylinders Filling Lot Identification Release Storage Chapter 18: Good Pharmaceutical Wholesaling Practice Principles General Requirements Storage Transport Page 60 of 60 MOST FREQUENTLY ASKED QUESTIONS Documentation and Control Chapter 19: Electronic Data Processing Principles Responsibilities Validation Security Chapter 20: Security Guidelines Principle Security Personnel Entry to Site Entry to Buildings Internal Security Chapter 21: Safety and Environmental Protection Principles Safety Environmental Procedures Chapter 22: Sterile Products Introduction Definitions Facilities Air Handling Systems Sanitisation and Monitoring Personnel Training Manufacturing Requirements and Controls Validation of Aseptic Process Sterilisation Processes Quality Control Finishing of Sterile Products Batch Release Chapter 23: Isolator Technology Principles Definition of Terms Isolator Design Principles The Siting of Isolators Factory Acceptance Test (FAT) Installation Qualification (IQ) Operational Qualification (OQ) Process Qualification (PQ) Microbiological Monitoring Sanitisation of Materials Page 61 of 61 MOST FREQUENTLY ASKED QUESTIONS Gas Sterilisation of Isolator Systems Chapter 24: Aerosols & Metered Dose Inhalers Principles General Premises & Equipment Production & Quality Control 191 What are the contents of Korean Drug Master File (KDMF)? Section 1.0 Contents Facilities of Manufacturing site 1.1 1.3 Drawings of the whole site plan (each production, laboratory, storage area and other accessory facilities for production should be labeled for area names, gates, and corridor) A simple plan showing the classification of the rooms (e.g Class I, II, III, IV) using different colors according to cleanliness Schematic Drawings of air-ventilation system 1.4 Schematic Drawings of Compressed air system 1.5 Schematic Drawings of water system including sanitation 1.2 2.0 Data on physico-chemical properties and stability 2.1 Data on physico-chemical properties 2.1.1 2.2 Origin, finding and developmental history (including when, where, from what and who extracted, isolated or synthesized the drug, what became the fundamental source of such finding and when and where the non-clinical studies and the clinical trial started) 2.1.2 Data on structure elucidation, physico-chemical properties and biological properties 2.1.3 In case any patent has been acquired in Korea or foreign countries, data including a copy of the patent register, etc Data on stability 2.2.1 2.2.2 As data in conformity with the "Guidance on Stability Test of Drugs, etc." as stipulated by the FDA Commissioner, specific analytical methods shall be described and raw data shall be attached Test Methods 2.2.2.1 2.2.2.2 Section For drug substances, long-term stability data and stressed condition stability data shall be submitted Stability data under the accelerated conditions may be submitted in place of the long-term stability data Contents Data on the manufacturing processes, packaging, containers, cautions in handling, etc Page 62 of 62 MOST FREQUENTLY ASKED QUESTIONS 3.1 3.2 3.3 Manufacturing processes 3.1.1 The overall manufacturing process flow shall be described in detail, and such description shall include matters relating to in-process controls by each manufacturing step And data on starting materials, solvents, reagents, etc used in each manufacturing process, such as synthesis (fermentation), isolation, purification, etc shall be attached 3.1.2 Detailed descriptions of key intermediates and information on their specifications and test method shall be attached Container Closure System (Packaging & Containers) 3.2.1 A description of packaging methods to assure stability and discussion on the suitability of the specific container closure system with respect to, for example, choice of materials, shall be specifically described 3.2.2 Market container system (packaging at release) shall be described Cautions in Handling Containers shall be categorized into well-closed container, tight container, a hermetic container and the like in order to assure stability, and specific storage conditions (i.e., to be stored in a dark place at room temperature or in the refrigerator at 2-3℃) shall be described together with the containers The shelf-life shall be set based on the stability data or any other data that can be officially acknowledged Data evidencing that manufacturing practice of the drug substance is in conformity with the Korea Good Manufacturing Practice (KGMP), Annex of the Enforcement Rule or anything equivalent thereto or higher 4.1 For this purpose, the document prepared in accordance with Form # 77 attached to the Enforcement Rule, or a copy of the certificate certifying that the practice is in conformity with Annex of the Enforcement Rule (In case the drug substances manufactured in a foreign country, the bulk GMP certificate issued by the government of the manufacturing country) shall be submitted Data on batch analysis for drug substances, analytical procedures, the solvents used, etc 5.1 Batch analysis shall be the results on the three or more consecutive lots in accordance with the applicable specification and test method 5.2 The analytical procedures shall mean the specifications and test methods for drug substances or intermediates and the method as specified in the Korean Pharmacopoeia or in the foreign official compendia acknowledged by the KFDA Commissioner shall be described For drug substances using any other methods than ones described in official compendia, an evidencing data shall be attached thereto 5.3 In case any organic solvent is used during the manufacturing process, data on the type of the organic solvent and the justification of the usage and the residual limits 3.3.1 4.0 5.0 Page 63 of 63 MOST FREQUENTLY ASKED QUESTIONS 6.0 of the organic solvent in the final product, the actual residual amount and the test method shall be attached thereto Sample drug substances as necessary for the quality test 6.1 The sample drug substances for the test of three times shall be provided unless otherwise justified 192 What you mean by site master file (SMF) and write its contents as per MHRA or PIC/S guidelines? The Site Master File is prepared by the manufacturer and contains specific information about the quality assurance, the production and/or quality control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings The Site Master File provides information on the manufacturer’s operations and procedures that can be useful in the efficient planning and undertaking of a GMP inspection S No C C Contents General Information C.1 C.1 C.1 C.1 Brief information on the firm (including name and address), relation to other sites and, particularly, any information relevant to understand the manufacturing operations C.2 C.2 C.2 Organization chart showing the arrangements for quality assurance, including production and quality control Pharmaceutical manufacturing activities as licensed by the Competent Authorities Any other manufacturing activities carried out on the site Name and exact address of the site, including telephone, fax and 24 hrs telephone numbers Type of actual products manufactured on the site and information about specifically toxic C.1 or hazardous substances handled, mentioning the way they are manufactured (in dedicated facilities or on a campaign basis) C.1 Short description of the site (size location and immediate environment and other manufacturing activities on the site) C.1 Number of employees engaged in the quality assurance, production, quality control, storage and distribution C.1 Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis C.1 Short description of the quality management system of the firm responsible for manufacture Personnel Qualification, Experience and Responsibilities of key personnel Outline of arrangements for basic and in-service training and how records are maintained Page 64 of 64 MOST FREQUENTLY ASKED QUESTIONS S No C C.2 Health Requirements for personnel in the production C.2 Personnel Hygiene requirements, including clothing Premises and Equipment C.3 C.3 C.3 C.3 C.3 C.3 C.3 C.3 C.3 C.3.1 C Nature of Construction and finishes Heat Ventilation & Air Conditioning System (HVAC) Handling of Toxic, Hazardous and Sensitizing Chemicals Brief description of water systems (schematic drawings of the systems are desirable) including sanitation Maintenance (description of planned preventive maintenance programmes and recording system Brief description of major production and control laboratories equipment Maintenance (description of planned preventative maintenance programmes and recording system) Qualification and calibration, including recording system Arrangements for computerized systems validation Availability of written specifications and procedures for cleaning manufacturing areas and equipment Arrangements for the preparation, revision and distribution of necessary documentation for manufacture Any other documentation related to product quality which is not mentioned elsewhere (e.g microbiological controls on air and water) Production / Manufacturing C.5 C.5 C.5 C.5 C.5 C Simple plan or descriptions of manufacturing areas with indication of scale architectural or engineering drawings are not required) Documentation C.4 C.4 C Contents Brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters (see at Appendix the list of products manufactured) Arrangements for the handling of starting materials Packaging materials, bulk and finished products, including sampling, quarantine, release and storage Arrangements for Reprocessing and Rework Arrangements for the Handling of Rejected Materials & Products Brief Description of General Policy for Process Validation Quality Control Page 65 of 65 MOST FREQUENTLY ASKED QUESTIONS S No C.6 C C Description of the Quality Control system and of the activities of the Quality Control Department Procedures for the release of finished products Contract Manufacturers and Analytical Laboratories Distribution, Compliance and Product Recall C.8 C.8 C Contents Arrangements and Recording System for Distribution Arrangements for handling of Complaints and Recalls Short description of the Self Inspection system 193 Describe about the Purified water system and validation? The purified water system consists of following pre-treatment before final production of purified water Pre-Treatment Reverse Osmosis (RO) Unit Electro De-ionization (EDI) System Ultra filtration, storage Pre-Treatment: Raw water is supplied from the APIIC (Andhra Pradesh State Industrial Infrastructure Corporation Ltd.) (Manjeera water) and is stored in raw water tank, then the raw water is chlorinated thereafter The chlorinated water is then transferred to the Pressure sand filter to remove the suspended solids and sodium Meta-bisulphite is dosed in the filtered water to neutralise any trace of residual chlorine present in the filtered water and to ensure complete de-chlorination This de-chlorinated is water passed through the softener to reduce the hardness and then passed through cartridge filter to remove the suspended solids, which may escape from up-steam units Reverse Osmosis (RO): The filter water is fed to the Reverse Osmosis Plant, and the water passes through three RO units The RO is a process for removing dissolved mineral salts, organic molecules and certain other impurities from water by forcing water under increased pressure to pass through a semi permeable membrane, from that RO system, water is fed to the EDI system Electro De-ionization (EDI) System: Electro deionization (EDI) is a common sense evolution of conventional ion exchange technology In Page 66 of 66 MOST FREQUENTLY ASKED QUESTIONS EDI, just as in conventional ion exchange, cations and anions in the feed water are exchanged for hydrogen and hydroxyl ions in the ion exchange resins, producing de-mineralized water The key operational difference is that with EDI, the ion exchange resin is regenerated continuously, while with conventional ion exchange, chemical regeneration is performed intermittently Continuous regeneration in EDI is achieved electrochemically by means of ion conducting membranes and an imposed electric current The hydrogen and hydroxyl ions necessary for regeneration are formed in-situ, without the addition of chemical reagents, by means of the familiar water dissociation reaction, sometimes called water splitting: H2O H+ + OHWith EDI, feed water is fed through ion exchange resin in the diluting chambers bordered by anion- and cation-conducting membranes At the same time, electrodes at each end of the unit impose an electric potential which drives the water splitting reaction and causes the ions in the ion exchange resins to migrate to the selectively permeable membranes, where they are transported into the adjacent concentrating chambers Once in the concentrating chambers, the ions are carried away by the concentrate flow Note that just as in conventional ion exchange, EDI benefits from the excellent mass transfer and de-ionizing characteristics of modern ion exchange resins ULTRA FILTRATION SYSTEM: The EDI permeate water passed through the series of seven ultra filtration membranes and will take care of bacteria, pyrogens, Total Organic Carbon (TOC) etc and is collected in Purified water Storage Tank From this storage tank the purified water is passed through UV lamp This water is again circulated and collected through return loop Raw Water Raw Water Storage Tank Micron Cartridge Filter Sodium hypo chlorite dosing Softener Pressure Sand Filter De - Chlorination Reverse Osmosis Unit Pre-Treatment Plant EDI System EDI Permeate Water Storage Tank Page 67 of 67 MOST FREQUENTLY ASKED QUESTIONS ULTRA FILTRATION (7 UF) Purified water Plant STORAGE TANK UV TREATMENT USER POINT The validation of purified water generation shall be done in three phases The purpose and sampling plan is described as below: The initial phase (phase-I) typically begins only after successfully completion of operational qualification The water generated during the second phases will be used for the manufacturing as long as the water meets the specifications PHASE- I During this phase daily samples were taken and analysed for chemical and microbiological quality Sampling should be after each step in the treatment process and from each point of use The incoming feed water will also be tested to verify the compliance with the specifications The phase-I shall be performed for a minimum period of 30days At the end of this phase alert and action limits will be established These alert and action limits will be used during phase-II and beyond The data obtained during phase-I should be used to develop the SOP and confirm that, the operational SOPs are adequate Alert and Action limits shall be calculated based on the phase-1 study PHASE- II This phase is to demonstrate that the system consistently operates within predetermined operating ranges and delivers the water of the required quality (as specified) when operated in accordance with the SOPs The sampling plan will be the same as phase -I, and this activity will continue for 30 days after completion of phase-I PHASE- III This phase will be continued for 10months to verify the extended performance of system procedures on the quantity and quality of water despite possible seasonal variations of feed water Page 68 of 68 MOST FREQUENTLY ASKED QUESTIONS At the end of this phase the performance qualification is considered as completed and on going monitoring will be established a continuous record of water quality This activity is under progress During this phase purified water samples are collected daily from minimum one point of use, covering all points in a week PHASE I II III PRIMARY OBJECTIVES Develop & Finalize operating, preventive maintenance, sanitization procedures Demonstrate production and delivery of water of the required quality To finalize the SOP on sanitization, Alert & Action Limit Demonstrate consistent operation within established ranges Demonstrate consistent production and delivery of water of the required quality Demonstrate extended performance Ensure that potential seasonal variations are evaluated and treated Phase-I: samples shall be collected daily from all user points and tested for chemical and Microbiological parameters Chemical parameters like pH, TOC, Conductivity, Nitrates and Heavy metals were tested For Microbiology use high nutrient and low nutrient media to isolate the stressed organism The rationale of being low nutrient agar (R2A) being used during the validation of purified water was to enumerate and isolate any adverse microorganisms, which are either slow growing or injured during preliminary stages of water treatment The bio-flim formed by the endogenous microorganism adsorbed on to the surface is also indicative of surviving in low nutrient medium The samples tested using high nutrient agar were incubated at 30-35°C for days and those tested using low nutrient agar were incubated at 20-25°C for days Analyse the sample as per the Standard Operating Procedure Phase-I will be started and duration of study is minimum 30 days Phase-II: samples shall be collected daily from all user points and tested for Chemical and Microbiological parameters Chemical parameters like pH, TOC, Conductivity, Nitrates and Heavy metals were tested For Microbiology use high nutrient and low nutrient media to isolate the stressed organism The rationale of being low nutrient agar (R2A) being used during the validation of purified water was to enumerate and isolate any adverse microorganisms, which are either slow growing or are injured during preliminary stages of water treatment The bioflim formed by the endogenous microorganism adsorbed on to the surface are also indicative of surviving in low nutrient medium The samples tested using high nutrient agar were incubated at 30-35°C for days and those tested using low nutrient agar were incubated at 20-25°C for days For Microbiology use high nutrient and low nutrient media to isolate the stressed organism Analyse the sample as per the Standard Operating Procedure Duration of Phase-II study is minimum 30 days Phase-III: samples are collected daily from minimum one point of use, covering all points in a week for Page 69 of 69 MOST FREQUENTLY ASKED QUESTIONS Chemical and Microbiological parameters For Microbiology use high nutrient media to isolate the stressed organism Analyse the sample as per the Standard Operating Procedure The samples tested using high nutrient agar was incubated at 30-35°C for days Duration of Phase-III study is 10 months which also includes the seasonal variations 194 What microbial & chemical parameters are to be considered during the nitrogen gas validation? 01 Sterility Test 02 Particulate Matter 03 should be sterile Black White Fibers Visual Particles NIL NIL NIL LBPC (In House) 10 - NMT 25/100 mL 25 - NMT 10/100 mL Non-viable particle count Maximum concentration limits for particles should be 0.5 = 1000/Ft3 & = 70/ Ft (ISO 8) 04 Bio burden Not more than 10cfu /100mL 05 Purity Not less than 99.5% (Based on manufacturer COA) 06 Oil mist Not more than 1.0 mg/m3 07 Moisture content Not more than 80 mg/m3 [* LBPC means “Liquid Born Particle Count] 195 What microbial & chemical parameters are to be considered during the compressed air validation? 01 Sterility Test 02 Particulate Matter 03 should be sterile Black White Fibers Visual Particles NIL NIL NIL LBPC (In House) 10 - NMT 25/100 mL 25 - NMT 10/100 mL Non-viable particle count Page 70 of 70 MOST FREQUENTLY ASKED QUESTIONS Maximum concentration limits for particles should be 0.5 = 1000/Ft3 & = 70/ Ft (ISO 8) 04 Bio burden Not more than 10cfu /100mL 05 Oil mist should be absent 06 Moisture content should be absent [* LBPC means “Liquid Born Particle Count] Page 71 of 71 ... you mean by ? ?Quality Assurance? ??? The sum total of the organized arrangements made with the objects of ensuring that all APIs are of the quality required for their intended use and the quality systems... we have SOPs? We have SOPs for the following areas: - Quality Assurance - Quality Control - Production Page 25 of 25 MOST FREQUENTLY ASKED QUESTIONS - Personnel - Warehouse - Safety & Environment... measures where required Quality audit because of: To assess the effectiveness of the quality management system Assessing conformance Page 10 of 10 MOST FREQUENTLY ASKED QUESTIONS Investigating