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OVERVIEW AND GENERAL CONCEPT OF QUALITY ASSURANCE
QUALITY ASSURANCE

Quality Assurance means:
1. Training & Development
2. Validation
3. Documentation & Maintenance
1. Training & Development:
1. The Quality Assurance chemist or officer should have undergone training to the extent necessary to ensure their competence in the skills required for planning, carrying out training to all the employees of other departments , conducting Qualifications, validations and reporting.
2. The training and experience should be documented individually and evaluated within the requirements of the applicable quality system of the Competent Authority
a. Basic training: Moreover, in order to be appointed as a quality Assurance officer, the candidates should demonstrate their knowledge of the relevant matters in the pharmaceutical field, including:
1. Good Manufacturing Practice and Good Distribution Practice
2. Principles of quality assurance and quality management systems
3. Technical aspects of pharmaceutical and API manufacturing (e.g. pharmaceutical
Technology, process and ventilation engineering, validation, computerized systems, analytical instrumentation, and microbiology).
4. Organization and quality systems of the Competent Authority/Inspectorate and training in
Working according to relevant national and Community SOPs and procedures related to
Pharma industry.
5. Interrelation of licensing, inspection, sampling and analysis.
6. Pharmaceutical Development, Quality Risk Management and Pharmaceutical Quality System (incl. ICH and EU guidelines).
7. International organizations their activities and documents (EDQM, ICH, PIC/S, WHO)
b. Further training
1. In addition to their basic training, new Quality Assurance Chemist or officer should be trained by senior Quality Assurance Chemist or officer.
2. The theory should be explained and the practice should be shown in the field, so that concrete examples of the meaning and of the goals of Quality Assurance are given and can be discussed.
3. New Quality Assurance Chemist or officer should participate, but only as observers, in on the spot Quality Assurance carried out during their initial training.
c. Continuous training
1. Considering the rapid implementation of new manufacturing technologies, the ever more frequent utilization of automatic and computerized systems both in production and quality control of medicinal products, Quality Assurance Chemist or officer should also receive continuous training.
2. This could be achieved through their participation in courses, seminars, scientific meetings and conferences organized either by the individual organizations or by national or international scientific organizations
3. Quality Assurance Chemist or officer should have their performance and qualifications periodically reviewed within the requirements of the applicable quality system of the Competent Authority.
4. Their competence should be maintained and updated by practical experience and by participating in courses, seminars, scientific meetings, conferences and through review of relevant publications.
5. This should be documented and its effectiveness assessed to ensure that
a. Knowledge of GMP, quality systems standards and requirements is current,
b. Knowledge of inspection procedures and methods is current,
c. Knowledge of quality assurance activities within the requirements of the applicable quality System of the Competent Authority is current.
2. Validation
1. Validation is defined as the process of establishing documentary evidence, which provides a high degree of assurance that a specific process will consistently produce a product and Equipment meeting its predetermined specifications and quality attributes.
2. To achieve validated status, a series of qualifications need to be undertaken.
3. How is Validation important
 Validation provides us assurance that:
a. The process is consistent
b. The system is performing consistently
c. Operating personnel comply to the systems & procedures
 The Management and Regulators need confidence and assurance
 The Regulatory approvals are based on the Quality systems which includes Validations as a key factor
 The Regulatory submissions guidelines demand submission of validation documents or a summary of the activities
 Validation includes the following
a. Equipment Qualifications
b. Computerized system validation
c. Manufacturing process validation
d. Method Validation
e. Water system validation
f. Steam
g. HVAC systems, etc………..
Validation History: Validation concepts were initially borrowed from the aerospace industry in 1960s
1. These concepts were first applied in the pharma industry in sterilization processes
2. Later applied in Solid-Dose forms with extremely low levels of active ingredients
3. Application of these concepts began to expand in 1970s
4. By 1980s, the concepts covered all pharma manufacturing processes
5. Validation concepts expanded with public statements, journal articles and through finalized guidelines
6. Original intent of validation was clear, to establish “Documented evidence that a process will consistently do what it purports to do”
3. Documentation & Maintenance:
Document:
1. Document is an organized form of data & information, revealing status of individual or several activities performed.
2. Usually referred for Qualification / Validation Document, Quality Agreement, Regulatory Dossier, Specifications, Test Methods, Technology Transfer document, Impurity Profile document, SOPs, STPs, Protocols etc…
Documentation:
1. Documentation is the process of generating data, reports and documents.
2. There are three fundamentally different types of documents used in the pharmaceutical industry:
a. Commitment Documents
b. Directive Documents
c. Data Collection Documents
a. Commitment documents includes
1) Regulatory Submission Documents
2) Master Plans
3) Requirement Documents
b. Directive documents include:
1) SOPs, STPs
2) Protocols
3) Specifications
4) Manufacturing Records/Procedures
5) Quality Maintenance and Monitoring Programs
c. Data collection documents include:
1) Forms
2) Batch Records
3) Log Books
4) Reports
5) Laboratory Notebooks
6) Raw data is an observation, result output, simple print-out e.g., weighing (gross, tare, net weight); print-out of temperatures; chromatographs, spectra, calibration values, PM checklist observations, etc.
7) Record is a Collection of data in a structured format, organized print chart, log sheet or log book
8) Report is a document providing conclusive information, drawn from raw data. A report is a certified document, e.g., CoA, Validation Report, Investigation Report, etc.
How does documentation help in Quality Assurance?
1. Documentation is the only objective evidence which demonstrates that the activity was performed
2. Documents help to assure that quality standards are consistently met
3. Documents provide traceability & linkages
4. Documents communicate quality standards to all who interact with the product
5. Documents interact in a manner that reduces redundancy and increases the flexibility of the system when changes occur
6. Reliable documentation is a control which raises assurance of the quality of the product manufactured
7. Documents are discrete packages of information assembled to ensure that accurate information is provided to those who need to know
8. If properly controlled, documents provide an opportunity to keep this information secure
9. Documents help to establish standard specifications and processes, direct the work and collect evidence which assures compliance with standard specifications and processes
10. Documents declare product standards and describe how to monitor, test and judge for compliance with these standards
11. Documents provide a consensus of purpose, direction and authorization for projects; they organize the work in a manner that assures efficient and effective work flow
12. Documents organize a complex set of tasks and direct the fulfillment of objectives
13. Documents like Master Plans are reliable predictors of GMP problems e.g., if a firm does not have a formal written validation plan, then it is impossible for the system to be in a state of validation
14. Well-written planning documents reflect favorably on the overall quality of a firm’s program
15. Documents like Protocols help in preventing manipulation of raw data
16. Documents like Specifications help in uniquely identifying and distinguishing an item from other similar items in the department, facility or company. They direct the testing/evaluation process that determines whether a product/component/material meets its identity characteristics and functional performance expectations
17. In order to provide the above assurances, it is absolutely necessary to have all activities well-documented - ADEQUATELY, APPROPRIATELY & ACCURATELY
Validation & Qualification:
1. The principles of qualification and validation which are applicable to the manufacture of medicinal products.
2. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, be validated. A risk assessment approach should be used to determine the scope and extent of validation.
3. The key elements of a validation programme be clearly defined and documented in a validation master plan (VMP) or equivalent documents.
4. The VMP be a summary document which is brief, concise and clear.
5. The VMP contain data on the following:
a. Validation policy;
b. Organizational structure of validation activities;
c. Summary of facilities, systems, equipment and processes to be validated;
d. Documentation format: the format to be used for protocols and reports;
e. Planning and scheduling;
f. Change control;
g. Reference to existing documents.
Validation Documentation
1. A written protocol should be established that specifies how qualification and validation will be conducted. The protocol be reviewed and approved. The protocol should specify critical steps and acceptance criteria.
2. A report that cross-references the qualification and/or validation protocol be prepared, summarizing the results obtained, commenting on any deviations observed, and drawings including the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification.
Qualification
Design Qualification
1. The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.
2. The first element of the validation for new facilities, systems or equipment is design qualification (DQ).
Installation Qualification
1. The documented verification that the facilities, systems and equipment, as installed or
2. Modified, comply with the approved design and the manufacturer’s recommendations.
3. Installation qualification (IQ) has to be performed on new or modified facilities, systems and equipment.
4. IQ includes the following:
1. Installation of equipment, piping, services and instrumentation has to be confirmed to the current engineering drawings and specifications;
2. Collection and collation of supplier operating and working instructions and maintenance requirements;
3. Calibration requirements;
4. Verification of materials of construction.
Operational Qualification
1. The documented verification that the facilities, systems and equipment, as installed or
2. Modified, perform as intended throughout the anticipated operating ranges.
3. Operational qualification (OQ) has to be performed after the successful completion of Installation qualification.
4. OQ includes the following:
a. Tests that have been developed from knowledge of processes, systems and equipment;
b. Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions.
5. The completion of a successful Operational qualification allows the finalization of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It permits a formal "release" of the facilities, systems and equipment.
Performance Qualification
1. The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.
2. Successful completion of Installation qualification and Operational qualification follows Performance qualification (PQ).
3. PQ includes the following:
a. tests, using production materials, qualified substitutes or simulated product, those have been developed from knowledge of the process and the facilities, systems or equipment;
b. Tests to include a condition or set of conditions encompassing upper and lower operating limits.
Qualification of established facilities, systems and equipment
1. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment.
2. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented for further use.
Process Validation:
1. The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.
2. Process validation applicable to the manufacture of pharmaceutical dosage forms.
3. They cover the initial validation of new processes, subsequent validation of modified processes and re-validation.
4. Process validation normally should be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation).
5. Processes in use for some time should also be validated (retrospective validation).
6. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated.
7. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner.
Prospective validation
1. Validation carried out before routine production of products intended for sale.
2. Prospective validation should include the following:
a. Short description of the process;
b. Summary of the critical processing steps to be investigated;
c. List of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status
d. finished product specifications for release;
e. List of analytical methods, as appropriate;
f. Proposed in-process controls with acceptance criteria;
g. Additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate;
h. sampling plan;
i. methods for recording and evaluating results
j. functions and responsibilities;
k. Proposed timetable.
3. Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions.
4. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation.
5. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters would constitute a validation of the process.
6. Batches made for process validation should be the same size as the intended industrial scale batches.
7. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and with the marketing authorization.
Concurrent Validation
1. Validation carried out during routine production of products intended for sale.
2. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts.
3. The decision to carry out concurrent validation must be justified, documented and approved by authorized personnel.
4. Documentation requirements for concurrent validation are the same as specified for prospective validation.
Retrospective validation
1. Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data.
2. Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.
3. Validation of such processes should be based on historical data.
4. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.
5. The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results.
6. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency.
7. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process.
8. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified.
Cleaning Validation:
1. Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.
2. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure.
3. The rationale for selecting limits of carryover of product residues, cleaning agents and microbial contamination should be logically based on the materials involved.
4. The limits should be achievable and verifiable.
5. Validated analytical methods having sensitivity to detect residues or contaminants should be used.
6. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.
7. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated.
8. Consideration should be given to noncontact parts.
9. The intervals between use and cleaning as well as cleaning and reuse should be validated.
10. Cleaning intervals and methods should be determined.
11. For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes.
12. A single validation study utilizing a “worst case” approach can be carried out which takes account of the critical issues.
13. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
14. "Test until clean". is not considered an appropriate alternative to cleaning validation
15. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.
Change control:
1. Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process.
2. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications.
3. All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted.
4. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation should be determined.
Revalidation:
1. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid.
2. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.