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Aseptic Processing: The New Guidance

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Aseptic Processing: The New Guidance


Paris December 2004
Ian Symonds
Special Thanks to: PQRI Team Richard M Johnson - Abbott Martin Van Triestse - Bayer
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History of the Guidance


Previous FDA Guidance ..1987 PDA Aseptic Points to Consider..Sept., 2002 FDA Concept Paper IssuedSept. 27, 2002 PDA Comments on Concept Paper.Oct. 22, 2002 PQRI Recommendation..Mar. 5, 2003 FDA Draft Guidance Issue...Aug. 22, 2003 PDA Comments Sent to FDA...Oct. 31, 2003 FDA Final Guidance Published..Sept. 29, 2004

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Participation in the Process


PDA has been a leader in aseptic processing
TR 22, 26, 34 Points to Consider Document PQRI Working Group Participation Numerous Conferences since Concept Paper Informal and Formal Comments offered at every stage

Since 2001 PDA has been actively engaged to influence this FDA guidance
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Lead-up to Final Guidance


More input from Industry Increasing focus on International harmonization Desire to increase clarity in guidance to promote greater inspectional consistency FDA focus on science- and risk-based principles

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Results
PDAs Points to Consider
37 are in agreement 5 are partially in agreement 1 is not in agreement 6 are not addressed

All PQRI Recommendations were Adopted PDA made 100 Comments


39 were adopted 19 alternates were adopted 52 were rejected
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Results
FDA's guidance documents do not establish legally enforceable responsibilities. Guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. Alternate approaches are acceptable with justification.
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Results
The use of the word should in Agency guidance means that something is suggested or recommended, but not required. There are more than 457 recommendations in the guidance. The document uses the word should 426 times.
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Key Elements
Use aseptic process only when terminal sterilization is not feasible Clarification of Dynamic conditions Adopts ISO air cleanliness classification system Alert & Action Levels vs Limits Unidirectional vs Laminar Flow

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Key Elements
Air velocity not specified but must be justified HEPA filtered air Aseptic process area detailed design recommendations Alternate methods can be used to test HEPA filters in the hot zones Supervisory and QCU oversight or aseptic personnel
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Key Elements
Protection of stoppered vials prior to capping Partially closed lyo stoppered vials within Class 100 Remove air from the autoclave chamber as part of a steam sterilization cycle Monitoring Critical Surfaces Critical surfaces and surfaces in close proximity should be sterilized
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Key Elements
Process simulations
operator fatigue size of run duration of run incubation temperatures acceptance criteria

Environmental monitoring trending

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Key Elements
Encourage use of advanced technologies
Rapid micro methods Isolators Aseptic automation

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Performing Process Simulation Using the New Guidance

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Process Simulation
Guidance Sections:
Study Design Frequency and Number of Runs Duration of Runs Size of Runs Line Speed Environmental Conditions Media Incubation and Examination of Media-Filled Units Interpretation of Test Results
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Process Simulation
Study Design
Key Points
Closely simulate aseptic manufacturing operations
Should be representative of the manufacturing process. Should not reflect a better condition than that present during the manufacturing process.

Should closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations. Rationale for the conditions and activities simulated during the media fill should be clearly defined.

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Process Simulation
(Study Design - Key Points Continued)

FDA recommends that the media fill program address applicable issues such as:
Factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue) Representative number, type, and complexity of normal interventions that occur with each run, as well as non-routine interventions and events (e.g., maintenance, stoppages, equipment adjustments) * Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically. (From section #3: Duration of Runs) Lyophilization, when applicable Aseptic assembly of equipment (e.g., at start-up, during processing)

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Process Simulation
(Study Design - Key Points Continued)
Number of personnel and their activities Representative number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients) or transfers Shift changes, breaks, and gown changes (when applicable) Type of aseptic equipment disconnections/connections Aseptic sample collections Line speed and configuration Weight checks Container closure systems (e.g., sizes, type, compatibility with equipment) Specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted before line clearance is mandated)
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Process Simulation
(Study Design - Key Points Continued)

As part of the media fill activity it is important to develop a documented study design that: reflects the activities that occur during the manufacturing operation. provides rationale for the study design.

A combination of media fill approaches may also be used (e.g. piggyback media fills performed after the completion of production lots, media fills where the line is run intermittently covering the full production time, etc.).

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Process Simulation
(Study Design - Key Points Continued)

In the guidance, a list of items that should be addressed in the study design is provided. This should not be viewed as an all inclusive list. The guidance stresses the study design and uses the term should be addressed. This is important in that the guidance gives the firm the responsibility to determine how a particular activity should be addressed.

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Process Simulation
Frequency and Number of Runs
Key Points
At least three consecutive separate successful runs be performed during initial line qualification. Subsequently, routine semi-annual qualification conducted for each processing line will evaluate the state of control of the aseptic process. When data indicates the process may not be in control:
If the investigation into a failing media fill is conclusive: Correct and repeat. (1 to 3 runs based on outcome of investigation) If the investigation is inconclusive: Correct possible causes and perform 3 media fills.
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Process Simulation
Duration of Runs
Key Points
Justify the duration used. While the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production operations, other appropriate models can be justified. The duration needs to be long enough to incorporate manipulations, interventions, and factors related to the actual duration of the media fill (i.e. operator fatigue). For operations that utilize manual filling, closing or excessive manual manipulations, the length should be no less than the routine operation.
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Process Simulation
Size of Run
Key Points
A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units. The number needs to be sufficient to allow the manipulations, interventions, and factors related to the actual duration of the media fill to be incorporated. 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. The design of the media fill should dictate the number needed. Running a higher number of vials does not negate poor study design.

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Process Simulation
Line Speed
Key Points The media fill program should adequately address the range of line speeds employed during production. Each media fill run should evaluate a single line speed, and the speed chosen should be justified. Line speed must be addressed in the media fill design.

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Process Simulation
Environmental Conditions
Key Points Media fills should be adequately representative of the conditions under which actual manufacturing operations are conducted. Special non-routine precautions to reduce the possibility of contamination in media fills is not appropriate. To the extent standard operating procedures permit stressful conditions (e.g., maximum number of personnel present and elevated activity level) should be included.
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Process Simulation
(Environmental Conditions - Key Points Continued)

Stressful conditions do not include artificially created environmental extremes, such as reconfiguration of HVAC systems to operate at worst-case limits. Stressing the HVAC system to create a worst case condition (e.g. high humidity levels) is not appropriate and can result in a subsequent loss of environmental control within the facility.

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Process Simulation
Media
Key Points 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) should be considered in special circumstances. The media selected should be demonstrated to promote growth of gram-positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms). The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates.

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Process Simulation
Incubation and Examination of Media-Filled Units
Key Points Media units should be incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture. Incubation conditions should be established in accord with the following general guidelines: Incubation temperature should be suitable for recovery of bioburden and environmental isolates and should at no time be outside the range of 20-35 oC. Incubation temperature should be maintained within +2.5 oC of the target temperature.

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Process Simulation
(Incubation and Examination of Media Filled Units Key Points Continued)

Incubation time should not be less than 14 days. If two temperatures are used for the incubation of the media filled units, the units should be incubated for at least 7 days at each temperature (starting with the lower temperature). Each media-filled unit should be examined for contamination by personnel with appropriate education, training, and experience in inspecting media fill units for microbiological contamination. If QC personnel do not perform the inspection, there should be QC unit oversight throughout any such examination.
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Process Simulation
(Incubation and Examination of Media Filled Units Key Points Continued)

Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected. After incubation is underway, any unit found to be damaged should be included in the data for the media fill run, because the units can be representative of drug product released to the market.

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Process Simulation
(Incubation and Examination of Media Filled Units Key Points Continued)

Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention type; quantity of units removed), providing for consistent production practices and assessment of these practices during media fills. If written procedures and batch documentation are adequate to describe an associated clearance, the intervention units removed during media fills do not need to be incubated. Procedures need to be clear if units are to be removed.

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Process Simulation
(Incubation and Examination of Media Filled Units Key Points Continued)

Where procedures lack specificity, there would be insufficient justification for exclusion of units removed during an intervention from incubation. In no case should more units be removed during a media fill intervention than would be cleared during a production run.

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Process Simulation
(Incubation and Examination of Media Filled Units Key Points Continued)

The ability of a media fill run to detect potential contamination from a given simulated activity should not be compromised by a large-scale line clearance. It is not appropriate to perform a planned large-scale line clearance that impacts vials associated with a planned simulated event or intervention. If an unplanned large-scale line clearance is required per procedure that impacts vials associated with a planned simulated event or intervention the simulated event or activity should be repeated.

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Process Simulation
Summary
Developing an overall study design for process simulations is the key. The design must support/represent the manufacturing activities performed. Use the guidance. It provides clear specific direction in a number of areas (eg. Number of units to be filled, incubation requirements, the exclusion of non-integral units, etc.). Think about the overall media fill design. To incorporate the many factors (interventions and events) to be studied, the design may need to incorporate the use of: Multiple media fills. A combination of media fill approaches (e.g. piggyback media fills performed after the completion of production lots, media fills where the line is run intermittently covering the full production time, etc.).
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9. Interpretation of Test Results


The process simulation run should be observed by the QC Unit, and contaminated units should be reconcilable with the approximate time and the activity being simulated during the media fill. Video recording of a media fill may serve as a useful aide in identifying personnel practices that could negatively affect the aseptic process.
The observer should take detailed notes that permit the correlation of activities and events during the media fill to possible positive units. This also would require identification of units filled by time.
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Video Recording
Video recording of process simulation is not required. Video recording of process simulations may be useful as an investigative tool in the evaluation of positive units, and/or aseptic training efficacy. The use of video recording is optional. Each manufacturer should have a procedure that defines the purpose of the video record, how its to be used, and its retention period.
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Video Recording

If video is used, be sure that: it is adequate to capture all of the activities; that it is reviewed not only for correlation to positives, but to give feedback on aseptic practices (regardless of positives); and that it is retained as raw data.
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Investigation of Positives
Any contaminated unit should be considered objectionable and investigated. The microorganisms should be identified to species level. The investigation should survey the possible causes of contamination.
Regardless of whether acceptance criteria is met, positives should be investigated. If possible, correlation of any positive should be linked to an action or failure of aseptic practice (that can be corrected).
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Investigation of Positives (cont.)


If the Acceptance criteria is not met:
Production may be suspended until appropriate actions have been documented. Product should not be released until the system is appropriately re-qualified. Any product manufactured following the media fill and prior to a successful re-qualification should receive appropriate management review that assesses the risk of non-sterility. Product produced by the process under evaluation prior to the media fill should also receive appropriate management review. Corrective and preventive action should be implemented where appropriate and the system re-qualified, as defined.

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Some examples of considerations for investigation include:


Microbial environmental monitoring data Equipment CIP cycles Sterilization cycles of media, commodities, and equipment HEPA filter evaluation (airborne particulate levels, filter media leak testing, velocity measurements, seals, age, etc.) Product and utility filter integrity Room airflow patterns and pressures Operator training and technique Unusual events that occurred during the media fill Identification of media fill and environmental isolates for purposes of identifying the potential source of contamination Particulate monitoring data Sanitization procedures Calibration condition of sterilization equipment Product sterility test results Product incubation studies Personnel monitoring data Analysis of interventions Engineering changes Maintenance activity Line history Storage conditions of sterile commodities, if applicable Media run history

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Impact on previous production


In addition, any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill. The investigation should consider the potential impact on previously produced product. A decision on whether or not to take action against product that has been previously manufactured and/or distributed, if applicable, should be made based upon evaluation of all the information available. This decision, with appropriate data, must be documented. This includes the generation of an exception document that justifies management's decision.
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Impact on previous production (cont.)

Consideration should consist of a risk assessment that includes:


Level of contamination Identification of contaminant(s) Review of preservatives in product, if any Results of investigation conducted Implications of media fill failure on other filling lines and products Results of the three re-qualification media fills including environmental control data associated with these runs, and Corrective action(s)
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Any positive
Whenever contamination exists in a media fill run, it should be considered indicative of a potential sterility assurance problem, regardless of run size. The number of contaminated units should not be expected to increase in a directly proportional manner with the number of vials in the media fill run. Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile.

The target is zero positives. Any positive unit indicates a potential sterility assurance problem, regardless of run size. All positives should be identified and should result in a thorough, documented investigation. If the positives are indicative of an unacceptable practice (e.g., a particular type of intervention) it should be corrected.
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Historical Perspective
1973 WHO - less than 0.3% contamination, which could be demonstrated with a fill of as low as 1,000 or 2,000 containers. 1980, PDA TM #2 - less than 0.1% contamination. FDA 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing, less than 0.1% in 3,000 units or more 1996 PDA TR #22 target of zero positives, small number of positives may be acceptable 1997/2003 EMEA Annex 1 - 0.1% at 95% CL 1998 ISO 13408-1 - 0.1% at 95% CL 2000 PIC/S 0.1% at 95% CL 2002/3 Canada - 0.1% at 95% CL
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Zero contamination level


Modern aseptic processing operations in suitably designed facilities have demonstrated a capability of meeting contamination levels approaching zero (Ref. 8, 9) and should normally yield no media fill contamination. Recommended criteria for assessing state of aseptic line control are as follows: Note: the acceptance criteria match the PQRI recommendations.
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PQRI Survey Data Summary:


Percentage of Media fills with contamination.(606 Media Fills Total)
Contaminated 9%

Not Contaminated 91%

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Breakdown of Contaminated Media Fills (54 of 606 runs contaminated).


1200 Contaminations 2%

5 Contaminations 4%

4 Contaminations 15%

3 Contaminations 7%

2 Contaminations 6%

1 Contamination 66%

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Acceptance Criteria
When filling fewer than 5000 units, no contaminated units should be detected. One (1) contaminated unit is considered cause for revalidation, following an investigation. Revalidation generally means 3 successful media fills
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Acceptance Criteria (cont.)


When filling from 5,000 to 10,000 units: One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill. Two (2) contaminated units are considered cause for revalidation, following investigation. Consideration should be based on some clear, consistent criteria. One such criterion could be whether previous media fills have also had positives.
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Acceptance Criteria (cont.)


When filling more than 10,000 units: One (1) contaminated unit should result in an investigation. Two (2) contaminated units are considered cause for revalidation, following investigation. Other considerations might depend on whether it is possible to link the positive with a specific action, that could be changed or is procedurally excluded.
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Intermittent positives
For any run size, intermittent incidents of microbial contamination in media filled runs can be indicative of a persistent low-level contamination problem that should be investigated. Accordingly, recurring incidents of contaminated units in media fills for an individual line, regardless of acceptance criteria, would be a signal of an adverse trend on the aseptic processing line that should lead to problem identification, correction, and revalidation.
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Limitations of test
A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit. The purpose of an aseptic process is to prevent any contamination. The use of growth promoting microbiological media in process simulations represents a situation that is far more rigorous than the actual process.
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Limitations of test
During the process simulation routine and non-routine

interventions are performed and the maximum number of operators are present. With few exceptions the product filled is less conducive to microbial proliferation (range of organisms and rate of growth) than the growth promoting microbiological media used. Many formulations such as preserved products and products with high or low pH could even be considered anti-microbial. This rigor also extends to certain steps that may be used in the actual process (i.e., lyophilization) that are not performed in the process simulation but are instead simulated due to their inherent detrimental effects on microorganisms.
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Limitations of test
A manufacturer is fully liable for the shipment of any nonsterile unit, an act that is prohibited under the FD&C Act (Section 301(a) 21 U.S.C. 331(a)). FDA also recognizes that there might be some scientific and technical limitations on how precisely and accurately process simulations can characterize a system of controls intended to exclude contamination. Through the use of growth promoting

microbiological media in process simulations, a very rigorous challenge of the process is achieved.

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Invalidating a media fill

TEST

As with any process validation run, it is important to note that invalidation of a media fill run should be a rare occurrence. A media fill run should be aborted only under circumstances in which written procedures require commercial lots to be equally handled. Supporting documentation and justification should be provided in such cases. Invalidation = no test Note: It is better to stop if unacceptable conditions occur, rather than to try to invalidate later.

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Invalidating a media fill- The following may be reasons to invalidate a process simulation:

TEST

Failure of growth promotion of media providing there are no positive units in the process simulation. Failure of the physical conditions in the aseptic processing area (e.g., power outage, failure of HEPA units). Failure of the operators to follow proper procedure in normal production that would lead to the discontinuation of a production batch.

Process simulations can be invalidated for any or all of the above reasons as well as other reasons, which according to procedure would also lead to discontinuation/rejection of a production batch. However, clear documentation of the event(s) that caused discontinuation of the process simulation should be performed and maintained.
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