Validation of Sterile Product

A PROJECT ON

VALIDATION OF STERILE PRODUCTS

SUBMITTED BY: NEETI MATHUR

VALIDATION Preamble: Validation is a key process for effective quality assurance. “Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes.” The major reasons for validation are:  Quality assurance – Quality cannot be assured by routine quality control testing because of limitation of statistical samples and the limited facilities of finished product testing. Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.  Economics – due to successful validation, there is a decrease in sampling and testing procedures and there are less number of product rejections and retesting. This leads to cost-saving benefits.  Compliance – For compliance to current good manufacturing practices, validation is essential. Phases of validation  Design qualification (DQ): documented verification of the design of

equipment and manufacturing facilities.  Installation qualification (IQ): documented verification of the system design and adherence to manufacturer’s recommendations.  Operational qualification (OQ): documented verification of equipment or system performance in the target operating range.  Process performance qualification (PQ): documented verification that equipment system operates as expected under routine production conditions. The operation is reproducible, reliable and in a state of control.

Type of Process Validation  Prospective Conducted prior to market the product.  Concurrent Based on information generated during actual implementation of the process. (Each batch will be released separately).  Retrospective (Not recommended for sterile product)

Based on accumulated historical production, testing and control data. Generally requires data from 10-30 batches. Use data only from batches made by the same process. VALIDATION OF STERILE PRODUCTS Main objectives:  To build sterility into a product.  To demonstrate to a certain maximum level of probability that the processing and sterilization methods have established sterility to all units of a product batch.  To provide greater assurance and support to all the results of the end products sterility test. Sterile Product: The Products which free of any viable organisms. Sterility: Viable microorganisms are absent. Bioburden: Total number of viable microorganisms on or in pharmaceutical product prior to sterilization.

Terminal Sterilization: Operation whereby the product is sterilized separately by autoclave after filled and packaged using sterilized container and closures in critical processing zones. Aseptic Operation: Operation whereby the product is sterilized separately by filtering through 0.2 μ or less filter then filled and packaged using sterilized containers and closures in critical processing zones. Validation Team: Production, QC, QA, Engineer, Planner  To prepare the validation protocol  Verify the calibration and maintenance status of equipment  Perform qualification for equipments and system  Verify change control  Schedule the validation activities  Training production operators  Conduct validation study  Monitor the critical steps in manufacturing process  Assure that the approved testing standard is being used  Evaluate all test results,  Prepare the validation report.

Pre-validation Requirements:  Preventive Maintenance for Facilities and Utilities  Calibration of Equipment  Cleaning Validation  Equipment & System Qualification  Raw Materials/Components/Test Methods  Process Justification  Change Control  Training operators

All must be proven suitable and reliable for the manufacturing process before the process can be validated.

Process Justification:  To identify critical process steps & process parameter of mixing process.  To determine the suitable Hold time Period  To confirm the analytical tests that will have to be performed  To define the optimal parameters throughout the overall ampoule filling process to consistently produce the finished products (filled ampoules) which meet the established specifications.  To assure that the product is sterile after sterilization process.

Validation Protocol A document stating how validation will be conducted, including test parameters, product characteristics, production equipment to be used and decision points on what constitutes acceptable test results.

Validation Protocol should contain:  Title Page, Review/Approval Page  Purpose and Overview  Equipment List  Ingredients and Component List  Qualification List of Equipment and System  Process Flow Diagram and Description  Equipment Critical Process Parameter  Process Validation Sampling Plan/Testing Requirements  Acceptance Criteria  Stability Requirements  Process for evaluation of any deviations occurring during validation  Conclusion

Equipment Critical Process Parameter:  Mixing Speed  Mixing Time  Gas flushing time  Type and size of filter  Filtering Time and Pressure used  Filling Speed  Temperature and Duration for Terminal Sterilization  Critical Manufacturing Step  Dissolving Step  pH adjustment step  Final mixing step  Filtering Step  Filling Step  Terminal Sterilization Step  Leak Test Step Critical Processing Parameter  Mixing Speed  Mixing Time  Flushing Time  pH Critical Processing Steps Dissolved active ingredients ↓ pH adjustment ↓ Final mixing ↓ Filtration ↓ Filling ↓

Sterilization

Acceptance criteria Dissolved active ingredients pH adjustment Final mixing Filtration Filling Sterilization Leak test Visual inspection

Clear solution pH within specification pH, appearance, assay, content, bioburden, hold time. Filter integrity, sterility, pH, hold time. Appearance, Bioburden, hold time, oxygen head space. Sterility, assay, pH, endotoxins etc. Number of leaked products. Number of defected products.

Product Testing  Validation testing of bulk and F/G must be based on testing standard release criteria and in-process testing criteria.  Typically involves non-routine sampling/testing throughout the entire process, with special emphasis on critical process parameters.  Routine QC release testing should be performed on a routine sample. These samples should be taken separately from the validation samples. Validation Batch:  New product and product transfer, Prospective validation is required  Manufacturing Process, Formula, Equipment and Batch Size have to be fixed during the validation trials.  Batch Size should be the same size as commercial production batch  The batch size must be fixed for production.  Different lots but same manufacturer of active ingredients should be used during validation trials.

Validation Batch: Bulk Sampling and Testing  Samples may be taken by  Collecting during Transfer  Using a sampling device  Take at least 2 samples at top, middle and bottom  Individual Testing of sample must be done and the result must meet the testing standard specification Qualification of Maximum Bulk Hold Time  The maximum period of time which the bulk can be held prior to filter, Fill and/or Sterilization  It will be counted after finished final mixing step until transfer to filter, finished filter until start filling and/or finished filling until start sterilization.  One full scale batch should be held for most practical maximum time period prior to filter, fill and/or sterilization  If there is not enough support information / qualification done. The period of 24 hours will be used.  Hold time qualification must simulate actual storage condition Finish Product Testing after Sterilization  Uniformity of filled volume  Perform testing on filled containers.  Sterility  10 samples from each of the beginning and end of the filling run. Samples must represent all filling nozzles.  Visual Evaluation  Appearance, Color of solution  Other Testing  Assay, pH, Density, Pyrogen or Endotoxin etc. Validation Report  Validation Team must prepare the report  Report must be reviewed and approved by QA.  Written Notification or either successful completion or failure of the process validation must be issued to top management.

 In case of failure, an investigation must be completed and

documented prior to repeat the validation study. Changes and Revalidation  Change of any of the following may need revalidation  Formula Composition  Raw Material Source  Manufacturing Process  Manufacturing Location  Equipments  Batch Size  Testing Specification Changes • Minor: It seems to have no impact on formulation It is not necessary to validate • Intermediate : It could have significant impact on formulation Depend on case-by-case (A minimum of 1 trial) • Major : It is likely to have significant impact on formulation Revalidation is required (A minimum of 3 trials) Minor Change  Qualitative inactive excipient change deemed minor by change control review  Process change deemed minor by change control review  Manufacturing location change with in same building, same equipment, personnel, procedure and utilities are used  Equipment change but same design, configuration. Intermediate Change  Active ingredient source or synthesis change deemed intermediate by change control review  Qualitative inactive excipient change deemed intermediate by change control review  Manufacturing location change to a different building on the same site and same utilities, same equipment, personnel, and procedure are used. Process changes, such as mixing times or operating speeds for solutions.

 Change in release specification to a tighter limit caused original

validation results to be out of specification  Extension of the qualified in process hold time for intermediate or finished product prior to packaging  Equipment change deemed intermediate by change control review

Major Changes  Quantitative or qualitative formulation change deemed major by change control review  Inactive excipient or active ingredient source change deemed major by change control review  Transfer product from on site to another  Significant change in process  Equipment change to a different design, configuration or operating principle. Conclusion  Validation Protocol identifies critical process parameters to be evaluated and predetermined acceptance criteria.  Process must be continually monitored and change control used to identify need for process revalidation.  Production and QA have to review and approve the validation result.  Product must be held until the validation get approval. Re-validation  Regular performance of process simulation studies.  Monitoring of environment, disinfection procedures, equipment cleaning and sterilization (including containers and closures).  Routine maintenance and re-qualification of equipment, e.g. autoclaves, ovens, HVAC (heating, ventilation and air conditioning) systems, water systems, etc.  Regular integrity testing of product filters, containers, closures and vent filters.  Re-validation after changes.

A. Process Simulations To ensure the sterility of products purporting to be sterile, both sterilization and aseptic filling and closing operations must be adequately validated. The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug, the container, and the closure) are brought together under conditions that contaminate any of those elements. Similarly, product sterility will be compromised if product elements are not sterile when they are assembled. The validation of an aseptic processing operation should include the use of a microbiological growth nutrient medium in place of the product. This has been termed a media fill or process simulation. In the normal media fill simulation, the nutrient medium should be exposed to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo. The sealed containers filled with the media are then incubated to detect microbial contamination. The results should be interpreted to determine the potential for a unit of drug product to become contaminated during actual operations (e.g., start-up, sterile ingredient additions, and aseptic connections, filling, and closing). Environmental monitoring data from the process simulation can also provide useful information for the processing line evaluation. 1. Study Design A recommended media fill program incorporates the contamination risk factors that occur on a production line, and accurately assesses the state of process control. The media fill program should address applicable issues such as:

 Factors associated with the longest permitted run on the processing line  Number and type of normal interventions, atypical interventions, unexpected events (e.g., maintenance), stoppages, equipment adjustments or transfers  Lyophilization, when applicable  Aseptic assembly of equipment (e.g., at start-up, during processing)  Number of personnel and their activities  Number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients)  shift changes, breaks, and gown changes (when applicable)  Number and type of aseptic equipment disconnections/connections  Aseptic sample collections  Line speed and configurations  Manual weight checks  Operator fatigue  Container closure systems (e.g., sizes, type, compatibility with equipment)  Specific provisions of aseptic processing related Standard Operating Procedures (e.g., conditions permitted before line clearance is mandated) A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. Media fills should not be used to justify an unacceptable practice. 2. Frequency and Number of Runs When a processing line is initially qualified, separate media fills should be repeated enough times to ensure that results are consistent and meaningful. This approach is important because a single run can be inconclusive, while multiple runs with divergent results signal a process that is not in control. At least three consecutive separate successful runs should be performed during initial line qualification. Subsequently, routine semi-annual qualification should be conducted for each processing line to evaluate the state of control

of the aseptic process. Activities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification. For example, the evaluation of a shift should address its unique time-related and operational features. All personnel who enter the aseptic processing area, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator's duties during routine production. Each change to a product or line change should be evaluated using a written change control system. Any changes or events that have the potential to affect the ability of the aseptic process to exclude contamination from the sterilized product should be assessed through additional media fills. For example, facility and equipment modifications, line configuration changes, significant changes in personnel, anomalies in environmental testing results, container closure system changes or, end product sterility testing showing contaminated products may be cause for revalidation of the system. Where data from a media fill indicate the process may not be in control, a comprehensive documented investigation should be conducted to determine the origin of the contamination and the scope of the problem. Once corrections are instituted, repeat process simulation runs should be performed to confirm that deficiencies in practices and procedures have been corrected and the process has returned to a state of control. When an investigation fails to reach well-supported, substantive conclusions as to the cause of the media fill failure, three consecutive successful runs and increased scrutiny (e.g., extra supervision, monitoring) of the production process should be implemented. 3. Duration of Runs The duration of aseptic processing operations is a major consideration in determining the size of the media fill run. Although the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production run, other appropriate models can be justified. In any study protocol, the duration of the run and the overall study design should adequately mimic worst-case operating conditions and cover all manipulations that are performed in the actual processing operation. In this regard, interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically.

While conventional manufacturing lines are highly automated, often operate at relatively high speeds, and are designed to limit operator intervention, there are some processes that include considerable operator involvement. When aseptic processing employs manual filling or closing, or extensive manual manipulations, the duration of the process simulation should generally be no less than the length of the actual manufacturing process to best simulate contamination risks posed by operators. For lyophilization operations, unsealed containers should be exposed to pressurization and partial evacuation of the chamber in a manner that simulates the process. Vials should not be frozen, as this may inhibit the growth of microorganisms. 4. Size of Runs The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination. A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units. For operations with production sizes under 5,000, the number of media filled units should equal the maximum batch size made on the processing line. When the possibility of contamination is higher based on the process design (e.g., manually intensive filling lines), a larger number of units, generally at or approaching the full production batch size, should be used. In contrast, a process conducted in an isolator can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation. Some batches are produced over multiple shifts or yield an unusually large number of units, and media fill size and duration are especially important considerations in the media fill protocol. These factors should be carefully considered when designing the simulation to adequately encompass conditions and any potential risks associated with the larger operation. 5. Line Speed The media fill program should adequately address the range of line speeds (e.g., by bracketing all vial sizes and fill volumes) employed during production. Each individual media fill run should evaluate a single worstcase line speed, and the speed chosen for each run during a study should be

justified. For example, use of high line speed is often most appropriate in the evaluation of manufacturing processes characterized by frequent interventions or a significant degree of manual manipulation. Use of slow line speed is generally appropriate for evaluating manufacturing processes characterized by prolonged exposure of the sterile drug product and container closures in the aseptic area.

6. Environmental Conditions Media fills should be adequately representative of the range of conditions under which actual manufacturing operations are conducted. An inaccurate assessment (making the process appear cleaner than it actually is) can result from conducting a media fill under extraordinary air particulate and microbial quality, or under production controls and precautions taken in preparation for the media fill. To the extent standard operating procedures permit stressful conditions, it is important that media fills include analogous challenges to support the validity of these studies. 7. Media In general, a microbiological growth medium, such as soybean casein digest medium, should be used. Use of anaerobic growth media (e.g., fluid thioglycollate medium) would be appropriate in special circumstances. The media selected should be demonstrated to promote growth of USP indicator microorganisms as well as representative isolates identified by environmental monitoring, personnel monitoring, and positive sterility test results. Positive control units should be inoculated with a