quality assurance and process control, documentation, validation

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Principles Of Production Management

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PRODUCTION MANAGEMENT & DOCUMENTATION Presented by RAJA SUNNY. J I, M. Pharm Presented to RAJASHEKAR. VALLURU PROFESSOR DEPT OF PHARMACEUTICS Dt:02/06/2011 EAST WEST COLLEGE OF PHARMACY

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Seminar on.. QUALITY ASSURANCE AND PROCESS CONTROL DOCUMENTATION VALIDATION

Quality Assurance:

Quality Assurance Quality : It can be defined as Fitness for use. Conformance to specifications or to some standard. Ability to fulfill the customers expectations & thereby provide satisfaction. Freedom from deficiencies. Philip Crosby defines quality as ‘to meet customers requirements’

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QA is the heart and soul of quality control. Definition: Activity of providing the evidences needed to establish confidence, among all concerned that the quality function is effectively being followed. QA = QC + GMP It consist of guaranteeing that a consumer can purchase a product with confidence and enjoy its satisfactory use for a long period. Need of central quality assurance system.

Principles of Quality Assurance:

Principles of Quality Assurance To achieve consumers trust the following principles must be followed: Adopt a 100% consumer first approach & obtain a firm grasp of consumers requirement. Hammer out a clear customer- first philosophy and ensure that everybody from the company president down is concerned with quality. Constantly rotate the quality cycle and never stop improving quality. Producers and marketers are responsible for QA. Follow ‘the next process is your customer’

Functions Of Quality Assurance Department:

Functions Of Quality Assurance Department Issue of batch production records. Review of batch production records. Review of quality control reports. Issue of product release certificates. Shop floor inspection. Upkeep of reference samples. Validations. Preparation & review of SOP’s. Self inspections. Complaint handling and investigations.

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Audit preparations. Vendors audit Audit of contract manufacturing unit. Trend charts. Salvaging. Training and development. Documentation. Check samples. Post production stability studies. Product recall.

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Issue of Batch Production Records The QA dept. issue BPR’s when the batch is planned for production. Batch no., signature, date of issue, BPR issue register. Review of batch production records . All BPR are received by QA immediately after the batch is completed. QA personnel checks Correctness of entries. Conformance to manufacturing instructions. Occurrence of deviations, if any deviations are found whether it has been made with proper authorization and documentation .

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4. Signature in all pages of BPR. 5. Presence of dispensing cards. 6. Calculation of yields. 7. Reconciliation of primary and secondary packing materials. 8. Signature of production manager. 9. Attachment of in-process reports. 10. Attachment of specimens of packing materials. After review of BPR sign & date of review will be written on BPR. Also finished product analysis report, microbiological report and product release certificate will be attached to BPR.

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Review of Quality Control Reports. All finished product analysis report are also received by QA after the analysis is completed by QC. Thoroughly checked against specifications. Batch will be released by only after the review of QC reports along with BPR’s by QA. Issue of product release certificates(PRC). Completed BPR will come to QA from production. If found satisfactory QA person give PRC no. in computer. After this material shifted from finished products(FP) stores to dispatch center. Then batch will be dispatched to various depots.

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Shop Floor Inspection Inspection consist of judging whether an individual document/lot is defective or non defective by comparing the test results with an acceptability criterion. Quality checked by: General monitoring. Production: a. Rechecking wt. Of dispensed materials. b. Observing processing operations. c. Checking BPR instruction. d. In process check e. Line clearance. f. Collection of in process & finished products. g. Inspection after packing. h. Checking of material/equipment sanitation prior to operations .

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3 . Packing: a. line clearance. b. checking of details on first pack. c. frequent in process check. d. random inspection of completed batches. e. checking of completed BPR’s. 4. Deviations: Any deviations observed in the manufacturing process are high lightened and necessary action will be taken by QA. 5. Co-ordination: Co-ordination between other departments is done for required information and timely release of batches

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InProcess control Parenterals: fill volume Clarity inspection. – glass particles – white & black particles. – particles of dust - fibers. Tablets: Uniformity in wt. Hardness Thickness Friability Disintegration test Packing sealing test.

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Liquid: fill volume Clarity of washing / washed water. Aerosols: Fill wt. Of active drug concentrate Fill wt of propellants Pressure Wt of container No of doses Dose evaluation.

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Up Keep of Reference Sample : The quantity sufficient for 2 analysis will be collected & kept in reference room. Records of date of collection, batch no., quantity, date of manufacture date of expiry are maintained. These samples are destroyed after 3 months after the expiry period of time. Validation : “to prove that process works” Determines process variables & acceptable limits for these variables and accordingly set up appropriate in process controls which specify alert and actions.

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Validation is a chain of activities which include Plan/protocol Installation qualification Operation qualification Performance qualification Report Certification Revalidation

Types of Validation:

Types of Validation Prospective validation. Concurrent validation. Retrospective validation. Equipment validation. Cleaning validation. validation includes all subjects like instruments, personnel, raw and packing materials, equipment design, installation, operation, critical support system ( water, steam, compressed air, inert gases, drainage) manufacturing process, analytical and quality procedures.

Preparation and Review of SOP’s:

Preparation and Review of SOP’s Definition of SOP : These are written instructions and procedures for carring out specific operations systematically and in accordance with the cGMP. Self inspection : Complaint handling and investigations. Objective is to investigate thoroughly and impartially regard less of nature &/or source of complaint

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Audit of contract manufacturing units. Trend charts : These are prepared for various quality and process parameters of all the batches manufactured during a particular year. Salvaging : finished goods are returned to central ware house from various depot due to - Received in soiled and damaged conditions - Completion of shelf life.

Training and Development:

Training and Development Basic principles are- Employee should know what he is supposed to do. Employee should know what is his influence on work. Employee should know result of his own work. Check samples: Evaluation of test results of check samples will contribute to judgement of quality level within manufacturing unit.

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Post production stability studies objective is to generate data that supports intended stability during the expiration time of the product and when necessary initiate proper action Product Recall : It is a speedy and efficient removal of unsatisfactory material from the market and assigning the responsibilities. Ex: May 2010 - Johnson & Johnson recalls 43 over-the-counter children's medicines made by McNeil Consumer Healthcare , a subsidiary of Johnson & Johnson, on April 30, 2010.

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The following parameters are considered for product recall. The health hazards that the user is likely to be exposed to because of product defect. The extent of recall i.e. consumer Retail Wholesale company’s own stock. 23

Responsibilities of QA and QC:

Responsibilities of QA and QC Serves as contact with regulatory agencies Final authority for product acceptance and rejection Identify and prepare the necessary standard operating procedures relative to the control of quality. During final product release it must be determined that the product meets all the applicable specifications and that it was manufactured according to internal standards & GMP. Major responsibility is a quality monitoring and audit function.

Documentation:

Documentation Document is a paper that provides information especially of an official or legal nature, written report or record. Documentation is a method of preparing a written material, which describes the process in terms of specifications, instructions etc. Documentation and records are essential for obtaining accreditation, certification of ISOs and approvals by Federal Bodies.

Importance Of Documentation of Records:

Importance Of Documentation of Records Provide working details necessary for manufacturing, packaging and QC. Reduce the risk of mistakes inherent in verbal communication. Help in tracing the deviation from the expected yields. Help in decreasing the batch to batch variations so that the quality of product kept within the limit of acceptability. Considered as history of batch operations. Self inspection of procedures in order to achieve better control of operations and improvement of product design.

Important Areas of Documentation:

Important Areas of Documentation Particulars with respect to their storage, stability & handling. Instructions of all manufacturing & packaging procedures, preferably batch wise are documented so that no further calculations are required at the work of floor level. Instructions for non product related operations such as cleaning & disinfections, maintenance of equipment, monitoring of working conditions use of specific conditions.

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Records such as batch manufacturing record, batch packaging record, test record for no product related operations as indicate. Procedures for testing for e.g. physical, chemical, microbiological. Etc. to be followed. Specifications of starting material packaging materials and product for the compliance by the quality control dept.

Components of Documentation:

Components of Documentation Numerical material identification system Master formula records Controls Master production and control records Batch production and control records Equipment cleaning and use of log book Records relating to container, closure and labeling. Production record review Distribution records Complaints files.

Numerical Material Identification System:

Numerical Material Identification System Numerical codes are a means of identifying and specifying the manufacturing lot/batch no. utilized in the production. Alfa numerical ordering system is used. Code number Application of number Item number Incoming raw materials, components Stock number Materials received from vendors & lot indication Control number Receipt of raw materials(active ingredients) Batch number Manufacturing cycle of a products Product number Product manufactured Packaging control number Packaging order

Master Formula Records:

Master Formula Records It is defined as written procedures that give the complete description of all aspects of its manufacture, packing and control with an intension to ensure the purity, identity, quality & strength of each dosage unit throughout the entire shelf life. Master formula includes Specifying a fixed formulation Identifying consistent quality criteria for components Providing an explicit set of manufacturing instructions Describing systematic sampling procedure Listing precise assays & tests Establishing methods for ensuring complete accountability for all material including packing and labeling

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Importance of master formula records for maintaining uniformity of product from batch to batch. Master production and control records are of two types The master formula which gives proportion of ingredients in the formulation. 2. Master batch formula, which specifies absolute amt. Of specific potent ingredient and excepients.

Controls:

Controls Control records are prepared by a competent individual and verified As well as endorsed for its correctness by an independent competent authority. Implementation of records Workers are expected to verify the relevant codes, instructions & accordingly perform the manufacturing operations . Amt. Entering into next manufacturing process is determined. Machine identification bar code is useful to control & identification of a process. After completion of operations, the persons performing, he/she has to sign in the records with date & time. These are further signed by supervisor

Master Production and Control Record:

Master Production and Control Record Name, strength, composition, physical and chemical description, method of administration. Name of active ingredient and excepients, total weight of dosage unit. List of components by names and codes. Weight/measure of each component. Calculated excess of component. Theoretical weight. Maximum %, Minimum% of theoretical yield. Description of containers, closures, labels, labeling packaging materials. Instructions, sampling testing procedures, specifications, special notations, precautions.

Batch Production and Control Records:

Batch Production and Control Records Batch production and control records are detailed description of instructions, procedures, controls & specifications for the production of a batch of drug product. Importance Serve as a manual (guide) for the actual production operations. Medium for recording all processes & procedures, which are required in pharmaceutical production. Serve as identification as to when they are performed by whom & where. Useful for verification in case of complaints on that batch.

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Equipment cleaning and use of log book. Records relating to container, closure and labeling. Production record review. Distribution records. Complaints file. - Receiving and recording of a complaints - Investigation of the complaints - Defect reporting.

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Document, Document, Document!!! In FDA-speak: “If it is not documented . . . it did not happen!” or, it’s a rumor!”

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VALIDATION Validation is attaining & documentation of sufficient evidence to give reasonable assurance, stating that equipment or process does & will do what it purports to do. According to ‘ US FDA’ “validation is establishing documented evidence which provides a higher degree of assurance that a specific process , equipment or facility meets its pre determined specifications & quality characteristics & will consistently produce a product of standard quality”

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Validation should begin in the designing stage for new facility & pre formulation stage for a new dosage form. In order to have a valid & qualified system it must be designed by qualified individuals only. As it is complex process, it is performed by individuals with necessary training & experience & who are themselves previously qualified. Engineering R&D Validation team QC QA MFG unit

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40 Engineering Install, qualify & certify plant facility, equipment &support systems. R&D Design, optimize, qualify manufacturing process with limits & specifications Manufacturing Operate & maintain plant facilities, equipments ,support systems, process and strictly follow SOP Q A Follow the validation protocol develop by Q.A & validate the incoming stock ,in process critical system &final product. Q C Establish approvable validation protocols &conduct process validation by monitoring ,sampling ,challenging the process & equipment

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Analytical test procedures Instrument calibration Critical support system Operators Raw materials Packaging materials Equipment Components Facilities of validation Manufacturing process Product design Utilities & services Records & reports

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Validation is of 4 types Prospective validation. Retrospective validation. Concurrent validation. Revalidation. Cleaning validation

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Prospective validation This is validation program executed before commercialization of a new drug/ formulation, to make sure that there are no potential hazards in full scale manufacture of product. Retrospective validation It is a program chosen for established products whose manufacturing process are considered stable (i.e. long history of state control operation). This method involves statistical analysis of numerical data obtained from different batches & then justify whether the system is qualified or not. The data includes MFR,BFR. b) assay values. End product test results. In process data.

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Different parameters checked in parenteral. pH value. Viscosity. Density. Color & clarity. Potency. Sterilization parameters . Different statistical methods are Basic statistics (mean , standard deviation, tolerance limit ) . Analysis of variance (ANOVA) . Regression analysis. Cumulative sum analysis. Control charting – most advance & useful.

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Concurrent validation This method includes in process monitoring of critical process steps & end product testing of current production along with documentation . This shows that the manufacturing is in state of control The same parameter of retrospective validation are evaluated with more stress on critical parameters affecting the process. Revalidation This method involves validation of facility which is previously validated when Change in critical component . Change in critical piece of equipment. Change in facility / plant (design / location ). Significant increased / decease in batch size. Sequential batches fail to meet product / process specifications

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CLEANING VALIDATION The objective is to minimize the possibility of significant cross contamination. It is considered that a cleaning procedure that consistently reduce the contaminant, to a level not exceeding one-thousandth of its lowest daily therapeutic dose is the highest daily therapeutic dose of the product, can be regarded as product validated. 46

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Validation of tablets Morphology: If the drug having different polymorphs, excepients may be used to prevent the change in physical forms. Material flow and compressibility: Drugs with poor flow or compressibility properties the excepients such as microcrystalline cellulose are used. Melting point: Drug has low melting point, a direct compression may needed to be developed instead of a wet granulation , that avoid the drug drying, potentially melting or degradation of drug.

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Process evaluation and selection Mixing and blending Physical factors that in creating a uniform mix or blend are bulk density, particle size, particle size distribution, surface area. Items to consider: Mixing or blending techniques Mixing or blending speed Mixing or blending time Excepient uniformity

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Wet Granulation Parameters to be considered during development and validation are: Binder addition Binder concentration Amount of binder solution Mixing time Granulation endpoint Wet milling: Factors to be considered Equipment size and capacity Screen size Mill speed Feed ratWet granulation: e

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Milling: It will reduce the particle size during the dried granulation. Factors to consider in milling are: mill type screen size mill speed feed rate Tablet compression : The materials being compressed will need to have adequate flow and compression properties for the good tablet dosage forms. factors to be considered are: tooling compression speed compression/ ejection force

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The following in process tests should be done during the compression of tablets: Appearance Hardness Tablet weight Friability Disintegration Testing of tablets Cracking or peeling of the coating Surface roughness Colour uniformity

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Tablet coating : Factors to be considered for tablet coating: Tablet properties Equipment type Coater load Pan speed Spray guns Application/spray rate Tablet flow Inlet/outlet temperature and airflow Coating solution

Validation of Parenterals:

Validation of Parenterals Parenterals are the sterile products that are validated to detect the sterility and the presence of microorganisms. Validation of parenterals can be done by Validation of facility design: selection of zone, differential pressure relative humidity temperature Personal and material flow Air filteration 55

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Validation of Process Product formulation filtration filling lyophilization packing Control and verification Environmental and personnel monitering aseptic filling simulations 56

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Finished product testing sterility testing particulate testing container closure integrity testing final product release testing staiblity testing Official test for Sterility testing:- Bacertial endotoxins test using LAL (limulus amoebocyte lysate ) test. LAL is a reagent for gel-clot formation. 57

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Pyrogen Test pyrogens are the metabolic products of microorganisms. This test is done to know the presence of pyrogens in the parenterals. De-pyrogenation method are as follows Adequate washing with detergent and followed by dry heat sterilization for glass wares. Distillation of water. Removal of pyrogens by using adsorbents(not widely used) 58

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Leaker’s test used for evaluating the efficiency of sealing process. Process involves immersing the ampules into the . solution containing Dyes(0.5-1% methylene blue) Labels on Parenteral Products Name of the preparation Route of administration Statement of storage conditions & expiration Name of the manufacturer & distributor Identifying lot number Amount of drug and excepients present. Volume of liquide to be added to dry preparation to prepare solution or suspension. 59

References:

References Theory And Practice Of Industrial Pharmacy By Leon Lachman, H.A. Liberman, Verghese Publication House, 3 rd Edition, Dader, Bombay. Remington Phamacy Practice..,Quality assurance And Process Control Documentation Basics That Support GMP By Carol Desain, Advanstar Communications, 1993. Robert. A. Nash, Pharmaceutical Process Validation..,pgno:159-189 www.google.com

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Thank you.. 