Aseptic Processing Survey, 2017

Aseptic Processing Survey, 2017

Apar Dholakia

References • 2017 PDA Aseptic Processing Survey • Sterile Drug Products Produced by Aseptic Processing – Curent Good Manufacturing Practices, 2004 • Points to be considered for aseptic processing Part 1 (2015) • The GMP Questions & Answers Guide Version 1.0, 2014 • ISO 14644-1:2015, Classification of air cleanliness by particle concentration • PIC/S, Isolators used for aseptic processing and sterility testing, Sept 2007. • PDA TR 34-1: 2001, Design and validation of isolator systems for the manufacturing and testing of healthcare products, • Google search…

Content • • • • • • •

Physical Environment Environmental Monitoring Aseptic process simulation Personnel Material & Material Transfer Cleaning , Disinfection and Sterilization Container Closure Integrity

Demographic information • All PDA members / Non-members • Total 304 respondents [Europe 35%, North America 30%, Australia/Asia 30%] • Type of product [SVP 74%{Biologics 42%, Ophthalmic/Otic 20%, Inhalers 8%, Ointment 4% Veterinary 7%, Device 15%}, LVP 36%]. • % Product manufactured using aseptic processing: 100% products: 49%, More than 75% product: 25%, 51-75% products: 10%.

General Outcome • Not to draw definitive conclusions but compilation of collective response • There is need for clarified guidance to address standardization of acceptance criteria to reduce risk of misunderstanding and redundant efforts. • It is important to harmonize technical and regulatory language and definitions.

Technologies (Existing) • Manual filling (Gowned person perform the majority of aseptic processing tasks) : 14% • Semi-automated filling (Containers are transferred from DHS by gowned person, filling, closing and sealing is performed by machine): 20% • Conventional filling: 48% • Advanced conventional (fill weight adjusted remotely): 27% • FFS/BFS: 11% • Closed isolator: 27% • Open isolator: 18% • RABs: 43%

Technologies (Way forward) • • • • •

Closed Isolators: 35% Open isolators: 28% RABs: 44% Robotic manipulation: 28% Closed vial technology: 5%

Environment •

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What is surrounding environment for closed isolator utilized for sterility testing? – ISO 5: 10% – ISO 6: 3% – ISO 7: 17% – ISO 8: 27% – CNC: 26% What is surrounding environment for open isolator utilized for aseptic filling? – ISO 5: 12% – ISO 6: 3% – ISO 7: 27% – ISO 8: 19% – CNC: 3% PDA TR34:01: 2001: “There need not be a specific particulate clean air classification requirement for the room surrounding isolators. The reader should be advised that some regulatory authorities may not agree with this perspective and will require aseptic production isolators to be placed in Class 100,000 (ISO Class 8) environments. There is, however, general consensus that sterility testing isolators need not be placed in a classified environment (USP 24 ). PIC/S : …of Grade D or better containing equipment called isolators providing a Grade A environment. When isolators are used for sterility testing there is no formal requirement for them to be placed in a Grade D environment. FDA, 2004: The classification of the environment surrounding the isolator should be based on the design of its interfaces (e.g., transfer ports), as well as the number of transfers into and out of the isolator. A Class 100,000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations.

Material and methods • What method do you use to decontaminate your isolator system? – – – – –

Chlorine Dioxide : 1% Hydrogen Peroxide Vapor : 76% Microcondensing Hydrogen Peroxide : 7% Liquid Hydrogen Peroxide : 7% Steam/ Hydrogen Peroxide : 7%

FDA 2004, “Normally a four to six log reduction can be justified depending on the application…”

Material and methods • If you surface decontaminate materials to bring into your isolator, what methods do you use? – Hydrogen Peroxide Vapor: 52% – Liquid sporicide applied automatically: 3% – Liquid sporicide applied manually: 38% – UV: 8%

• RABs – Do you allow interventions in the aseptic environment other than through the permanently installed gloves or half suit? – Yes: 46% – No: 54%

Physical Environment • What is environment in operation surrounding the class 100/ISO 5 area used for aseptic processing? – Grade A: 13%, Grade B: 71%, Grade C: 10%, Other: 6%

• At which location do you perform airflow visualization studies to evaluate airflow pattern in operation al condition? – Grade A: 96%, – Grade B cleanrooms to verify flow from cleaner to less clean area: 58%, – Entry way to classified areas: 34%, Other: 5%

Physical Environment • What data does your firm consider when initially establishing monitoring alert/action level for a new area? – Historical database : 72%, Cleanroom qualification: 12%, Sterilization studies : 1%, Publications: 1%, media fills: 5%, QRM: 6%

• What frequency does your firm use for re-evaluating environmental monitoring levels? – Less than annually : 16%, Annually: 66%, More than annually: 18%,

• PDA TR13, “action levels will be driven by the regulatory or industry guidelines while the alert levels may be driven by historical analysis of the environmental monitoring data”. • USP 1115, – “Studies on active microbiological air samplers indicate that variability of as high as tenfold is possible among commonly used sampling devices…” – “Because of the limited accuracy and precision of microbial growth and recovery assays, analysts can consider the frequency with which contamination is detected rather than absolute numbers of cfu detected in any single sample. Also, a cfu is not a direct enumeration of microorganisms present but rather is a measure of contamination that may have originated from a clump of organisms.”

HEPA filters Testing • What is the frequency with which HEPA filters in critical areas (i.e. Grade A) tested. – ≥6 months 76%, 12 months: 21%, > 12 months : 2%.

• What is the frequency with which HEPA filters in other areas tested. – ≥6 months 32%, 12 months: 55%, > 12 months : 11%.

HEPA Filter Repair • Can HEPA filters be patched if they are used in critical areas (i.e. Grade A)? – No: 64%; – Yes, with a maximum limit for single patch size: 24%, – Yes, with no limit: 3%, – Yes, with maximum patch size determined by aggregated patches: 9% • Can HEPA filters be patched if they are used in Grade B and Grade C  No: 42%,  Yes, with a maximum limit for single patch size: 42%,  Yes, with no limit: 4%,  Yes, with maximum patch size determined by aggregated patches: 12%

HEPA Filter Repair • IEST RP-CC001.5, Section 8.3.2, “.. not to exceed 13cm2 (2 in.2) in any one patch, or total of 1% of the areas being patched..” • EN 1822-4, Section 8.5 “.. not to exceed 3cm2 in any one patch, or total of 0.5% (Not including frame) of the areas being patched..” • ISO14644-3, “by agreement between the customer and suppler”. • IEST RP-CC034.4 in various sections states: “Field repair should not block or restrict more than an additional 3.0% of the filter face area, and no single repair should have a lesser dimension exceeding 3.8 cm (1.5 in.). • FDA - Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice 2004, Section 4.D.2 allows HEPA filters to be repaired in (undefined) limited areas when appropriate. • A general recommendation is that, at minimum, the filter be replaced when the pressure drop reaches two times the initial pressure drop

Airflow velocity •

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Where should airflow velocity be taken, with respect to a filling line or other aseptic operations? – Locations where meaningful and reproducible results can be obtained. Typically at distance of 15-30 cm from filter face. Is an airflow velocity of 0.45m/s±20% a requirement at the working surface of critical filling zone? – Yes for EU Annex 1. – US: Velocity required at distance of 15-30 cm (6 inches) from filter face, not at working height. – For Isolator, (PDA TR 34-1: 2001) ”air velocity and air exchange can be significantly lower than in a conventional clean room” PIC/S, “The lower air velocity generated by the laminar or unidirectional option may reduce risks of venturi effects and impacts on production operations”. FDA 2004, HEPA-filtered4 air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area

Environment Monitoring • Is 5 micron particle sampling performed? If so, how is the data evaluated? – Yes, action level and alert level are set: 76% – Yes, results are trended and evaluated: 20%

• Should limits be applied for ≥5µm particle monitoring for Grade A environment? – Limit should not be applied for ≥5µm particle monitoring for Grade A environment. When companies count particles ≥5µm separately, they should focus on the overall trend rather than individual numbers based on the low accuracy of the measurement.

Environment Monitoring • ISO 14644-1:2015, sample collection limitations in low concentrations and potential particle losses in the sampling system makes ≥5µm particle monitoring inappropriate. • As per FDA Q&A 2014, “It is generally not acceptable from a current good manufacturing practice (“cGMP”) perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 146441 Part 1: Classification of Air Cleanliness (“14644-1”) and ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 (“14644-2”) when qualifying their facility…” • FDA 2004, Reference of ISO 14644-1 is available.

Environment monitoring • How frequently do you sample your APA for presence of anaerobic organism? – Daily: 13%, Weekly: 12%, Monthly: 5%, Quarterly: 10%, Semiannually: 12%, Annually: 8%, Not at all: 40%. • If you test your APA environment for presence of anaerobic organism, is this a result of potentially anaerobic process condition? – Yes: 35%, No: 65%. • Which incubation regimen does your firm use for environment monitoring? – A single temperature within range of 20 – 35oC for three to seven days: 26%, Two temperatures : 20-25oC and 30-35oC in sequence: 61%, Two temperatures : 30-35oC and 20-25oC in sequence: 12%.

Environment Monitoring • Should environmental monitoring alert and action levels be considered specifications? – Environmental monitoring alert and action levels should not be considered specifications. However, any contamination in Grade A or surrounding Grade B area or on product contact surface shall be investigated. • When and under what conditions should gloves be monitored or changed? – Risk based. – Monitoring: After intervention involving inappropriate contact with product; Upon exit; as necessary. – Change: Tear/rips/gaps (with recording in document); after finger impression on plate; as necessary

Environment Monitoring • Who shall perform environment monitoring? – Trained and qualified quality or production personnel can perform environment monitoring – Personnel shall receive training on good sampling practices, with internal audit, unannounced monitoring or random verification of sampling by an independent quality unit.

Personnel • What is process to qualify personnel to work in or access the aseptic processing area? (Grade A/B) – Training: Basic GMP; Hygiene; Basic microbiology; aseptic technique; cleanroom behavior; gowning training & certification; relevant intervention procedure. – Initial : Manual media manipulation or with aseptic process simulation OR Participation in APS which they perform the same function(s), to the same extent.. – Periodic: Participation in APS which they perform the same function(s), to the same extent at least once in a year + Knowledge of successful gowning and microbial monitoring

Personnel • How are personnel qualified to work in APA? – Participation in media fill, work function: 92%. – Participation in media fill only, not work function: 8% – Demonstration of functional skills other than media fill: 46% • What is degree of oversight necessary to effectively monitor an aseptic process area? – Physical presence in the area (eg. Monitoring the areas through windows/ camera) – Degree of oversight may depend on physical separation/automation – Cleaning, maintenance, production in all shifts, or any activity that can negatively impact aseptic operation.

Aseptic Process Simulation • If a process simulation fails on a validated production line, what action do you take regards to product manufactured on the line? – Release: 0%, Based on investigation: 5%, – Release only after an investigation that determines root cause and one or more successful media fill: 88%, – Reject/recall : 3% • How are your process simulation distributed among different shifts? – Equally distributed across shifts: 69%, – According to production volume: 14%, – According to process risks: 9%.

Aseptic Process Simulation • If different filling setups and/or closure systems are utilized on a filling line, will your process simulation program address all combination? – Yes: 37%. – Participation in media fill only, not work function: 8% – Demonstration of functional skills other than media fill: 46% • How do you determine aseptic process simulation unit fill volume? – We use production fill volume: 24%. – Less than production fill volume : 13% – Adjust fill volume to allow for enough head space to allow growth: 16% – Adjust volume to fill enough volume to coat interior surface and show evidence of contamination: 35%

Aseptic Process Simulation • Do you use exactly the same compounding, filling and filtration equipment in conducting aseptic process simulation that you use in actual production? – Yes: 84%. – No: 7% • When performing process simulation trials, do you retain sterile media in sterile holding vessels to simulate standard manufacturing holding times prior to filling? – Yes: 78% – No: 22%

Aseptic Process Simulation • Do you utilize the same filling line speed for process simulations as utilized in production for that container? – Yes: 43% – No, speed equal to the slowest/highest normal fill speed: 4% – Risk based approach: 19% – More than one speed: 14% • Do your firm perform periodic re-qualification of bulk container/vessel sterile hold time? – Yes: 75% – No: 25%

Aseptic Process Simulation • How does your firm deal with interventions? – List of intervention for routine manufacturing maintained: 50% – A risk based assessment of intervention is performed to plan their inclusion in process simulation: 30% – Include a grouping of interventions of similar nature: 20% • Is the frequency of interventions included in the process simulation justified based upon a risk assessment? – Yes : 81% – No : 19% • Are the interventions in routine manufacturing periodically compared to those interventions included in periodic APS to update the APS program? – Yes : 98% – No : 2%

Aseptic Process Simulation • If a new corrective intervention is performed during production, how is it addressed? – Deviation: 70% – Compared to similar interventions performed during media fills: 49% – QRM: 61% – Product released and intervention included in next media fill: 43% – Product quarantined untill intervention included in next media fill: 17% • Do you routinely retain video of process simulation operations? – As any other GMP document: 33% – Until media fill is read and approved: 17% – Until next media fill: 5% – For more than one year of media fill: 20%

Aseptic Process Simulation • In conducting growth promotion studies, do you use only pharmaceutical test organism? – Only USP: 54% – USP + EM isolate: 74% • One EM isolate: 29% • Two EM Isolates: 29% • Three EM Isolates: 22% • More than four EM isolates: 14% • Do you incubate non-integral damaged container (Loose or missing stoppers, cracks)? – No: 69% – Yes, with segregation: 23% •

FDA Q&A 2014, Designing an effective cleaning program involves setting specific standards, understanding the facility’s microbial environmental isolates, and selecting the right disinfecting agents to inactivate isolates that may be in the product or in the environment…. While the use of environmental isolates in addition to the specified compendia cultures is acceptable, the use of environmental isolates alone is not acceptable.

Aseptic Process Simulation • What is target reconciliation of integral units for process simulation? – 100% reconciliation:62% – Same as commercial production: 18%

Thank you