Aseptic Filling Process Validation...
Information & Training. | Product and Process Validation
Aseptic Filling Process Validation:• All Aseptic Filling Process Validation studies must be performed in accordance with pre-approved protocols.
• Testing facilities, test equipment, instrumentation and test methodology must be fit for purpose and available when required.
• The clean rooms must be fit for purpose (as defined in pre-approved specifications) and available for use.
• The clean room standard which is defined in the protocols must be assured through initial qualification and on-going testing, in-process control and monitoring.
• All those involved in the validation must be fully competent based on training, experience and/or previous qualifications.
• All data and information generated during the validation needs to be documented, reviewed and certified as evaluated against predetermined criteria.
• All processing equipment should be properly installed and maintained.
• When all the above are in place, the aseptic process filling may be validated by means of process simulation (or media fill) studies.
• A comprehensive revalidation plan needs to be documented and implemented.
• A complete documented record of the validation process needs to be created and maintained.
The Aseptic Filling Validation protocol.The pre-approved protocol should contain the following:
• A clearly defined purpose, and scope of the study to be performed.
• A clearly defined definition of the process, equipment, what is to be studied, with details of performance characteristics.
• Clearly defined set of responsibilities: who is to review, approve, perform, analyze, evaluate each stage of the protocol.
• What are the content and format requirements for the validation report ?
• Are there other SOP’s, reference standards which need to be used – identify and define.
• What are the test methodologies, test equipment and test materials which are to be used.
• If new equipment is required, then installation and qualification requirements are to be documented.
• Will current equipment need to be updated ? If yes, why, and an outline of the changes required and how any upgrade will be verified.
• Detailed, step by step statement of actions to be taken in performing the studies.
• Test equipment calibration requirements, and finally…
• Define the “Acceptance criteria” which will determine the acceptability or otherwise of the final aseptic process protocol report.
Test Equipment & Laboratory Equipment (Aseptic Filling):• All measuring & recording instruments used in the studies must be fit for purpose. This includes accuracy, repeatability, linearity, robustness, ease of use considerations. Equipment must be calibrated in accordance with defined written procedures, before any validation studies commence.
• If the laboratory is internal to the manufacturing facility, it must be verified that the lab staff are competent to perform the testing, appropriate equipment must be available, the environment within the room must be as required by the defined SOP’s or standards referenced.
• If an external laboratory is to be used, there needs to be a means by which the competence of the external laboratory facility and personnel is determined in advance. This may be by verification of laboratory accreditation or by means of an audit prior to or during the testing.
• Detailed, approved, written procedures, defining the relevant, validated methodologies that are to be carried out during the course of the study need to be available and referenced in the validation study protocol.
Qualification and on-going maintenance of equipment
All equipment to be used in an aseptic process validation study must be:
• Verified as conforming to build requirements which are defined in the Installation Validation.
• Verified as having been correctly installed, and supplied with the required services and support equipment and facilities (often defined in the Operations Validation)
• Verified as being able to operate as required in routine Production under stressed (worst case within limits) conditions (often defined in the Performance Validation).
• For on-going manufacture, a comprehensive preventative maintenance program must be implemented
Staff considerations:The individuals involved in conducting validation studies need to be competent by means of training, education and experience. This includes not only the process operators, but technical, engineering staff and all staff who may impact on the final protocol outcome.
• It is important that the same competence levels proposed for manufacturing apply to the validation, i.e. it is not acceptable to only use the highly skilled operators for the validation then use newly trained employees during production.
• All staff must be trained in the fundamentals of cGMP. Personal hygiene requirements must be defined and explained. Any relevant microbiology impacts may also need to be included in training, and critically important the hazards associated with product contamination must form part of training.
• The gowning procedures used in the validation must be the same as those planned or used in routine production.
• In order to validate under worst case conditions, the maximum number of individuals who are likely to be in the clean room needs to be identified and should be present during the validation. You need to consider exception circumstances here, e.g. will there be extra individuals during customer visits. etc? .
• Clean room operators involved in validation studies must be microbiologically monitored by means of taking samples from gloves, gowns etc. as per normal production.
Maintaining the clean room – requirements:The process Validation study needs to be performed under the exact same environmental conditions that will apply during normal production.
• The clean room needs to be certified as conforming to the defined requirements. Such defined requirements may be outlined in an environmental specification. Aspects to be considered include:
Air change rate, particle counts, pressure differentials and air flows within the clean room
Air filter integrity tests & air velocity at each air filter.
Light, heat and humidity requirements/limits.
Particle count requirements.
What are the requirements for individual work stations within the clean room? Again similar considerations as per the clean room itself.
• An ongoing testing and certification regime needs to be planned and implemented, the frequency will be defined as per any re-calibration, maintenance, revalidation based on criticality, reliability considerations etc.….
• Environmental monitoring – Air Filter testing, air velocity, pressure differentials, air changes, particle counts of the room and individual work stations.
• Microbiological monitoring – Bio-burden checks, determination of the number of viable organisms per cubic meter of air, checking of the microbiological quality of surfaces.
In addition to the above there also needs to be ongoing testing of:• Work surfaces, clean room walls and doors via a planned program of cleaning & disinfection.
• Where a liquid is to be sterilized by filtration, filter integrity testing of the filters used to sterilize must be performed. This must (at a minimum) be performed after the use of the filters.
Studies of Media Fills for aseptic solution products:
• A liquid microbial nutrient growth medium is prepared, and processed in a manner which resembles as close a possible the normal manufacturing process. The sealed containers of medium finally produced are subsequently incubated under defined conditions and then examined for evidence of microbial growth. The resultant measure indicates the level of contamination per unit of media.
• The growth medium used must meet the following criteria:
Filterability: If there is a filtration stage in the process, the liquid medium should be capable of being filtered through the same grade of microbial retentive filter as that through which the actual product is filtered.
Selectivity: The growth medium must have low selectivity so that it supports the widest possible range of micro organisms growth.
Clarity: The growth medium needs to be as clear as possible to facilitate subsequent checking for any growth following incubation.
• All units filled and incubated should be visually examined for growth (turbidy) after approximately two weeks of incubation (usually a minimum of 14 days). The incubation temperature would normally be 25 to 35 deg. C. The exact conditions will depend on the medium and should be defined in the test protocols.
Media Fill (Aseptic Filling) Acceptance Criteria:• While the media fill test is widely used and accepted a major problem arises with determining the acceptance criteria.
• Industry wide an acceptance criteria of not more than one fail in 1000 (0.1%) of contaminated media filled units is often applied.
• Application of a 1 in 10,000 (0.01%) acceptance criteria may be more appropriate and would give a greater confidence level, however, such a level of testing may not be practical in terms of facility resources, laboratory time, people resources etc..
Need for revalidation:• As with all forms of retesting be it – re-calibrations, routine repeat maintenance, re-certification, the frequency and extent of the revalidation will be determined by the criticality of the product, the frequency of change of the product, stability of the process, stability of product inputs etc.
• Normal industry practice for an aseptic filling process is for revalidation to be twice per year, however, any significant changes to equipment, processes, personnel, facilities, would necessitate retesting.
Review of information gathered during performance of the protocol:• All information gathered needs to be documented and included in the protocol study report. This data needs to be reviewed and evaluated by the appropriate personnel against the defined acceptance criteria. “Appropriate personnel” should be defined in advance in the validation protocol.
• Any deviations from expected results need to be investigated and reported on, with the results of the investigation documented.
• Any deviations from the test plan as outlined in the protocol need to be clearly explained.
• Personnel records of training, experience, and/or education, demonstrating the required competence of all personnel involved in the studies.
• Records identifying those individuals involved at all the key stages of the study.
• Documented evidence that the all product, materials, components, equipment, etc., used in the studies were fully sterilized by validated sterilization processes.
• Copies of all relevant Standard Operating Procedures, specifications and relevant standards used or referenced in the validation.
• Documented evidence of the evaluation of the results.
• Identification of any deviations including the investigation, analysis and impact assessment related to any such deviation.
• The completed, approved, signed Process Validation Report.
Information & Training.
Product and Process Validation.
- Validation versus Verification
- Integration of Risk into Validation
- Validation Gap Analysis
- Implementing a Validation Process (IQ, OQ, PQ)
- The Validation Master Plan (VMP)
- Validation during the Design processes
- Software Validation
- Cleaning Validation
- Cleaning Process Sampling and Test Methods
- Documentation Management for Validation compliance
- Equipment, Component, Material and Facility Validation
- Implementation of a re-Validation process
- Protocol Reporting
- Implementation of the Audit process to assure Validation effectiveness
- How to ensure that Validation activity is appropriately documented, reviewed and aligned with requirements.
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