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1) The document discusses quality assurance and its importance in pharmaceutical manufacturing. It covers topics like quality systems, total quality management, quality assurance in pharmaceutical production, and compliance with Good Manufacturing Practices.
2) Quality assurance aims to ensure that each drug batch meets specifications and is safe, effective and acceptable for its intended use. It involves establishing controls before, during and after production to guarantee product quality.
3) Key elements of a quality assurance system include quality planning, product development, vendor control, validation, documentation, and quality audits to ensure manufacturing and quality control procedures are followed properly. This helps increase production standards, regulatory compliance and reduce defects.
1) The document discusses quality assurance and its importance in pharmaceutical manufacturing. It covers topics like quality systems, total quality management, quality assurance in pharmaceutical production, and compliance with Good Manufacturing Practices.
2) Quality assurance aims to ensure that each drug batch meets specifications and is safe, effective and acceptable for its intended use. It involves establishing controls before, during and after production to guarantee product quality.
3) Key elements of a quality assurance system include quality planning, product development, vendor control, validation, documentation, and quality audits to ensure manufacturing and quality control procedures are followed properly. This helps increase production standards, regulatory compliance and reduce defects.
1) The document discusses quality assurance and its importance in pharmaceutical manufacturing. It covers topics like quality systems, total quality management, quality assurance in pharmaceutical production, and compliance with Good Manufacturing Practices.
2) Quality assurance aims to ensure that each drug batch meets specifications and is safe, effective and acceptable for its intended use. It involves establishing controls before, during and after production to guarantee product quality.
3) Key elements of a quality assurance system include quality planning, product development, vendor control, validation, documentation, and quality audits to ensure manufacturing and quality control procedures are followed properly. This helps increase production standards, regulatory compliance and reduce defects.
Presented By: Dabhi Ajay S. M. Pharm L. M. C. P. Ahmedabad
Dept. of Pharmaceutics and Pharmaceutical Technology
List of Contents:
Quality - Reasons and characteristic of quality - 5Ms of quality and factors influencing quality
Quality Assurance - Components and Elements of QA - QA systems - Fundamental features and benefits of QA system - TQM - QA in pharmaceutical manufacturing - Process deviations and failures - Change controls - QA in R&D - Concept of SQC - Sampling and sampling plans
Quality: represents both function and process.
Function: there are operational groups whose major responsibilities are to assure quality creation and maintenance (QA) and to monitor the specifications established to control activities (QC)
Process: set of activities and operations which determine whether a pharmaceutical product has quality.
Quality is spelled in terms of specifications which are in language easy to understand and have methods for measuring, determining or assessing and also for verification Quality??
Reasons for quality consciousness in society:
Increasing consumer awareness : Expectations are growing in consumers
Liberalization of economy : Competition is growing
Globalization of market (shrinking world)
International standards (ISO 9000)
Quality tag
Characteristic of quality:
IDENTITY PURITY POTENCY STRENGTH UNIFORMITY SAFETY EFFICACY STABILITY A drug product should comply with such requirements within the permitted tolerance limit and that up to designated or expected shelf life period of the drug in question. It should also comply with legal and professional standards. Quality is affected during the process of manufacturing on handling and therefore required to conform with specified quality form the beginning till they are consumed
Quality cannot be merely justified by the end product testing and nor by manufacturing and quality control assessment
Quality is the end product of a thoroughly understood, properly designed, implemented and controlled manufacturing processes.
Customary sample size alone cannot verify that the various factors in the system intended to assure quality within and between batches of product are functioning as they were designed to function. The 5Ms of Quality Man
Material
Machinery
Manuals/Methodology ( SOP)
Motivation
Factors influencing quality: Pre analytical Analytical Post analytical Right specimen Laboratory professionals Recording Right collection Reagents Interpretation Right labeling Equipment Turnaround time Right quantity Selection of test - SOP Report to right user Right transport Records Right storage Bio-Safety Quality Assurance:
Assurance: Guarantee or promise given to inspire confidence Quality Assurance is sum total of the organized arrangements made with the objectives of ensuring that product will be of quality required by their intended use. QA is the activity of providing to all, concerned the evidence needed to establish confidence that quality function is being performed adequately.
Aim of QA: To ensure that each batch of a medicinal product complies with its specifications and is fit for its intended use in terms of safety, efficacy, and acceptability. Quality assurance Definition
It is the sum total of all lab activities that are undertaken to ensure generation of accurate and reliable results.
What is the Objective? To ensure credibility of the lab and generate confidence in lab results
Components of Quality assurance Internal Quality control: IQC
Nature: Concurrent performed by: lab staff Objective: Reliable results on a daily basis
External quality assessment: EQA Nature: Retrospective to evaluate IQC Performed by: Independent agency Objective: Ensure inter laboratory comparability
Elements of QA: Quality System Planning: A management responsibility include strong management, facilities, equipments, personnel, control etc.
Product development
Vendor control
Validation: Validation of process, Analytical method, facilities, equipments, personnel, raw materials, product, environment etc.
Documentation
Quality Audit: Periodic reviews and evaluation of manufacture and quality control.
Quality Assurance System:
A quality assurance system is constructed by merging a series of actions. These actions collectively ensure product quality. The QA system must:
1) establish specific activities before production
2) control factors during production
3) evaluate results following production
Quality systems
Objectives To prevent risks To detect deviations To correct errors To improve efficiency To reduce costs
How : By establishing a quality manual defining Organizational structure Staff Responsibilities Procedures and processes Resources Documentation
Fundamental features of quality system:
a quality policy which defines the purpose and objectives of the pharmaceutical manufacturing facility, it also outlines the ways in which these objectives will be achieved.
resources which include materials, equipments and personnel
documentations which includes procedures and standards
an audit process to provide assurance that procedures have been compiled with; this process can also be used to improve the quality system.
In pharmaceutical production process, with assurance is involved in the following activities:
Purchasing Dispatching Warehousing Operational protocols Manufacturing Training Quality control Validation Packaging
The system for each the listed activities must provide:
assurance that materials, product labeling and storage have conformed to an established programme of operations.
Monitoring to ensure that the system is completed with or updated.
Benefits of QA system:
Higher standards of production Compliance with regulatory requirements Reduce waste Less risk of product defects
Quality System:
Ensure quality Provide evidence Generate confidence
Total Quality Management:
Quality function is part of a team composed of research, production Marketing/sales, and customer service. It requires total commitment of senior-level management and supervision of all departments, operators, suppliers and customers. Raw materials must be characterized and then purchased Facilities must be designed, constructed and controlled Equipment must be selected Personnel must be trained Distribution department is responsible for controlling the shipping and handling of products, using inventory control system based on FIFO. Marketing department should be sensitive to customer needs and be responsive to complaints.
QA in Pharmaceutical Manufacturing: GMPs
- QA is ubiquitous in production - Quality unit is responsible for ensuring that controls are implemented during manufacturing operations which assures drug product quality. - The quality model that these regulations establish consists of a sequence of events of: Qualification Validation Specifications Monitoring End of process testing Written instructions Documentation and monitoring review Decision (to approve or reject) Qualification: includes essentially activities performed to prove that a system does what it purpots to do 1. Design qualification 2. Installation qualification 3. Operational qualification 4. Performance qualification
- should establish and provide documentary evidence that the premises, the supporting utilities, the equipment and the processes will consistently produce a product meeting its pre- determined specifications and quality attributes.
- PQ should include, but not be limited to the following: tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; tests to include a condition or set of conditions encompassing upper and lower operating limits. New Facility, Utility and/or Equipment Qualification or Requalification Maintain in the qualified state Facility, Utility and/or Equipment retired from Change controls Extensive Monitoring Preventive Maintenance Calibration programme Construction and installation QA/safety approval to use Close out qualification package Qualification life cycle: Specifications: - Results of the validation and qualification exercises are specifications - They should be derived form previous acceptable process average process variability estimates where possible - It separates acceptability and unacceptability Monitoring: - Whether specifications are being met is the process of monitoring Documentation: -Procedure, master production and control records - Data recording documentation - Review of records, retention of records and follow-up of problems arising after production
Technology Transfer: -Technology transfer includes quality involvement - So QA oversights, review and approves (rejects) the transfer Facilities and Equipments: QA role can be review of:
Layouts and floor plans with regard to material, personnel, waste flow, and the potential for cross contamination
Materials of construction and design of all areas
Suitability of utilities, services, and the systems (adherence to GMPs and generally acceptable practices) for water, HVAC, gases etc.
Suitability of equipments (design, capacity, materials of construction, compatibility with process materials and conditions, ability to be cleaned and/or sterilized)
Qualification and validation of facilities, equipments, utilities etc. Materials:
-To test them to ensure that they have necessary quality attributes
- To segregate acceptable from unaccepted
-To maintain the quality of materials during their presence in the plant and in their processing
Documentation control: -Documents are specific for the process, product, equipment etc.
-QA issues, retrieves, reviews, and stores the documents
-SOPs and batch records must be authorized by a sign off procedure that includes group responsible for the procedure, all the groups directly impacted by the procedure, and QA.
-QA may be responsible for assigning batch numbers and expiration dates as a part of issuance of batch record.
-For SOPs, calibration logs, and the like standard distribution lists are necessary to ensure that all who need to use procedures receive updates at the same time with instructions as to the effective date of the new document as to the destruction or return of the old.
-review of documents after the completion of the process and testing. The batch record should be reviewed for completeness, proper sequencing, appropriate dates, acceptable yields, meeting of all in-process specifications, and explained and unexplained deviations.
-Final test results must be reviewed to ascertain whether all the specifications are met. If any results are not within specifications, the SOP to handle this must be implemented.
- After all these QA decides the releasibility of the final product.
Equipments Facilities Process Containers, Closures, Labeling, Raw materials Staff Product Purchase order Diagrams and drawings Batch records Purchase orders CVs Inventories
Diagram manuals Floor plans Reconciliati ons Monitoring Receiving records Inventories Job description s Training Sampling, testing Release documents Use logs Qualificatio ns and validations In process tests Sampling, testing Regulatory Master specificarti on sheet
Cleaning logs Monitoring records Control charts Reconciliati ons and accountabil ity Distribution In process Items control: Quality Assurance before start up Environmental and microbiological control and sanitation Manufacturing working formula procedures Raw materials Manufacturing equipments
Quality assurance at start up Raw material processing Compounding Packing materials control Label controls
Finished product control
Quality Events:
-Things didnt go as planned
- Events affecting quality should be investigated in a timely manner under the auspices of QA.
-Technical service dept. is responsible for performing the studies but QA must access the impact upon the affected batches and other potentially affected batches
- Annual review of products Process Validation Deviations and Failures: -It is foolhardy to begin process validation without an assurance that the process is under control - Recognize validation failure - well documented investigations for less clear deviations
The following steps should be performed as soon as possible after the problem is discovered: Document clearly what occurred and when it occurred.
Interview personnel as soon as possible (before memories can get clouded) and document the interview.
Collect any additional data (as is relevant).
Describe a sequence of events of when and what happened, review batch records, and corroborate events through data and records.
Process Materials Finished products Process deviations Specification deviations Product complaints Process condition deviation Unapproved vendors Adverse events In-process specification deviations Stability problems Specification deviation Environmental excursions Water, gases, etc. deviations SQC trends SPC trends Stability problems, recalls, reworks, returns Document any and all remedial actions that may have been taken.
List all possible causes for the event.
After investigating, eliminate causes that do not fit the data.
Establish a cause or most probable cause based upon the data.
List corrective actions that need to be implemented.
Only events that are not process-related could be written off as not negatively affecting the validation (e.g., power failures, natural disasters, human error, etc.).
Even if a process validation failed and the cause was not process-related, the validation should be replaced with a fresh run.
Change control: A basic change control system should cover:
Planned changes: change in equipment, facilities, utilities, and computer systems, temporary changes or emergency changes against permanent ones, changes in batch records and SOPs, changes in analytical test methods, specifications and raw materials. -planned changes are intentional and pre-approved and can be either permanent or temporary.
Unplanned changes: They are actually deviations -A change control SOP defining terms, levels of justification and approval needed, and the specific responsibility of approvers, must be written approved and followed.
-There should be a documented change control system -A technical review by qualified personnel should review the - adequacy of the justification - whether validation or revalidation is needed - the adequacy, accuracy, and usefulness of any requested drawings - the potential risk(s) (including cost and downtime), and whether those risks are adequately addressed.
-QA normally reviews proposed changes for the - adequacy of the rationale for the decision to make the change - compliance to the change control policy - assurance that adequate documentation of the change is present - the impact on internal or external customers or GMPs, and the required changes to other procedures, specifications, batch records, and so on.
- A Financial review - Follow up
- Emergency changes Emergency or quick changes still require writing the change down and getting the approval of one technical area manager (such as Development) and QA.
How to do change control?
1. Keep it simple: use an approved from and SOP 2. Hold regular change control meetings 3. Distribute proposed changes electronically 4. Train your employees 5. Follow up 6. Publish a report on outstanding change request forms 7. Be careful how you agree to handle temporary changes 8. Enlist a powerful ally and assign responsibility for tracking/monitoring changes to one individual / department. Monitoring: - Process and environmental monitoring - testing and issuance of results - Imp: results of testing is reviewed by QA. Thus QA must receive all notices of deviations and monitoring excursions on an on-going basis in such a way that it can make determinations as to product quality and what steps may need to be take. Inspection Control: - These are online QA staff responsible for container and label accountability, online statistical process control of critical processing steps, online checking of labels lines for expiration dates, batch no., and proper labels as well as line clearance before and after labeling run, filled vial inspections for particulates, tablet weight variation and other functions. Training: - Necessary in 3 areas of all plant personnel: regulatory, procedural, and technical. Auditing: - The essence of audit is comparison. The essential question of any audit are: 1) Has the system been established? 2) Is the system reasonable and appropriate? 3) If so, is it being followed?
- Manufacturing audit program should include: Vendors and contractors Plant inspection Procedures Batch records Submissions (pre-approval) Quality systems QA and QC Formulate the question Draw Conclusions Select or develop analytical procedure Optimize procedure Conduct analysis: Sampling Sampling preparation Analysis Reporting and Interpretation QA in Research and Development Goals of R&D
Effective drugs - data should be real, accurate, complete, consistent and reasonable - results of attendant analyses are the basis for companies and regulatory agencies decisions, must be unbiased, inclusive of all appropriate data, and in correct with the predetermined protocols and/or analytical plans.
assess the acceptability of and minimize the errors in products of R&D, thats submission and individual reports. GLPs: -Detailed, documented evidences of the appropriate functioning of the controls and assurance function is necessary to prove that the studies have quality and integrity. Preclinical QA: The quality aspects relate to the establishment of: The design of studies Investigational materials Test subjects Data that result from all tests Observations Gross postmortem pathology and histopathology and Preparation of report Audits: 1. Protocol Audits 2. Procedure audits - Study specific - System oriented 3. Documentation audits 4. Report audits 5. Facilities audits SQC: - Monitoring of quality by application of statistical methods in all stages of production - Used for estimating parameters, for performing test of significance, for determining the relationship between factors, and for making meaningful decisions on the basis of experimental evidence - SQC has been used to serve 1. as a basis for improved evaluation of materials through more representative sampling techniques and 2. as a means of achieving sharper controls in certain manufacturing process
Objective: determine whether the major source of observed variation is due to chance variation which is inevitable during the manufacturing process, or to assignable cause which is usually detected and corrected -For this normal frequency distribution curves and quality control charts have been used
Sampling and sampling plans: -Process of removing an appropriate number of items form a population in order to make inferences to the entire population - proper methods of sampling and adequate number and size of samples are needed for an effective QA program, as judgment of accept or reject lies in it - the number of unacceptable units are controlled to rigid standards by the stringency of the sampling plan -Sampling plans based on data from measurement of attributes or variables may be constructed -Govt. sampling plans such as MIL-STD-414 for variable sampling and MIL-STD-105D for attribute sampling is used -Acceptability of a batch is determined by the use of sampling plans associated with the designated acceptable quality level
- A sampling plan indicates the no, of units of product form each batch to be inspected and the criteria for determining the acceptability of the batch - Inspection level determines the relationship between the batch size and the sample size - Single sampling: specified sample is selected - Double sampling: a second sample for inspection is permitted if The first fails, and two acceptance numbers are used- the first Applying to the observed number of defectives for the first sample, And the second applying to the observed number of defectives for First and second samples combined - Statistical sampling plan requires that four basic quality standards Be specified: 1. An acceptable quality level (AQL) 2. An unacceptable quality level (UQL) 3. Risk or error (producers risk): probability of rejecting a good batch 4. Risk or error (consumers risk): probability of accepting a bad batch