Notes on International Standard ISO 13408-1: 1998(E)

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One of the main International Standards used as a reference document in a sterile pharmaceutical microbiology laboratory is ISO13408 – Aseptic Processing of Health Care Products .  Long ago, I reviewed the 1998 edition.  The 2008 edition of the standard was last reviewed and confirmed in 2011 as current.  Part 1 details the general requirements.  The 2008 edition is edition 2 and is a techncial revision of the 1998 document.  The guts of the standard are not dissimilar to version 1.

My review of the 1998 edition follows.  When I get my hands on the 2008 edition, I’ll review that with reference to this review.

The use of italics is my way of emphasising points.

SECTION 2: DEFINITIONS

APA = Aseptic Processing Area

  • Section 2.10 page 2: ‘bioburden’ is defined as: population of viable microorganisms on materials or in a health care product or package prior to sterilisation. This is important to note as we call bulk product that has passed through a sterilisation filter, and not filled as a bioburden.
  • Section 2.17 page 3: ‘disinfectant’ is defined as: chemical or physical agent that inactivates vegetative microorganisms but not necessarily highly resistant spores
  • Section 2.23 page 3: ‘media fill’ is defined as: method of evaluating an aseptic process using a microbial growth medium…media fills are understood to be synonymous to process simulation tests, simulated product fills, simulated filling operations, broth trials, broth fills, etc.”
  • Section 2.26 page 4: ‘product sterilising filter’ is defined as: porous material with a nominal rating of less than or equal to 0.22mm, capable of retaining a defined number of microorganisms using defined challenge test and conditions.
  • Section 2.29 page 4: ‘sterile’ is defined as “state of being free from viable microorganisms. NOTE: in practice, no such absolute statement regarding the absence of microorganisms can be proven”
  • Section 2.30 page 4: ‘sterilisation’ is defined as “validated process used to render a product free from viable microorganisms. NOTE: The number of microorganisms that survive a sterilisation process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero.”

SECTION 3: QUALITY MANAGEMENT SYSTEMS

  • The Quality Management system is governed by the requirements in ISO 9001 and/or ISO 9002 unless a superseding national, regional or international GMP is employed.

SECTION 4: PERSONNEL

  • Section 4.1.2 Page 5: The effectiveness of the defined procedures shall be evaluated at defined intervals (with respect to personnel training).
  • Section 4.2.2 Page 5 discusses training of operators with reference to,”emergency procedures to protect product quality, eg. Loss of HVAC system, loss of power etc”.
  • Section 4.2.3 Page 6states “…personnel, who require temporary access to the APA (aseptic processing area) shall be accompanied at all times by a person train and qualified in accordance with 4.2.2…”
  • Section 4.2.5 Page 6 states: All personnel that directly participate in the filling of manufacture of sterile products in the critical processing zones shall have taken part in a media fill that meets the requirements of this part of ISA 13408 at least once per year.”
  • Section 4.2.6 Page 6 states: “new personnel…shall take part in at least one…media fill…before being permitted to participate in processes carried out in critical process zones.”
  • Section 4.3 Page 6: General employee health notes: Initial and periodic medical examinations should be performed for individuals assigned to aseptic processing.
  • Section 4.4 Page 7…”microbiological monitoring program…sampling of…garments and gloves.”
  • Section 4.4.2 Page 7: “results of the (personnel) monitoring program shall be used to identify trends and evaluate the need for retraining.

SECTION 5: FACILITY DESIGN

Section 5.1 Facility design features

  • Section 5.1 part c) page 8: avoidance of ledges and other horizontal surfaces which can collect particles or disturb air flow
  • NOTE 1 page 8: The location of the APA relative to other areas within a manufacturing facility should be given full consideration, and the rationale for its location should be documented.
  • NOTE 2 page 8: In multipurpose facilities, the APA should be located away from high traffic areas (materials, equipment and personnel) or separated by physical barriers.
  • NOTE 3 page 3: Appropriate facility design should be considered when sensitising agents, cytotoxics or other hazardous materials are processed within the APA.

Section 5.2 Facility design review

  • Section 5.2.1 page 8: “A facility design review…conducted and documented to demonstrate that the facility design is consistent with product specific requirements…”
  • Section 5.2.2 page 8: “This…shall be applied retrospectively to existing facilities”

Section 5.3 Material flow

  • Page 8: “Aseptic processing facilities shall be designed to promote a controlled flow of components and materials in order to:…prevent mingling of clean and dirty items.”

SECTION 7: SUPPORT AREAS OUTSIDE THE APA

  • Section 7.1 page 9: “NOTE 2 The disinfection and environmental monitoring of this area (Class 100 000) may be less frequent than that utilised for the processing zones.”
  • Section 7.2 page 9: “Support areas shall be monitored routinely for the presence of microorganisms, i.e. environmental flora/isolates”

SECTION 9: GOWNING

Section 9.2 Gowning requirements

  • Section 9.2.1 page 10: “Personnel shall wear dedicated factory clothing, including shoes, prior to entering the gowning area.
  • Section 9.2.1 page 11 “NOTE 2 Personnel may change into dedicated factory clothing in the airlock adjacent to the gowning area.”
  • Section 9.2.2 page 11 “NOTE A mesh hair net and beard cover, if required, are donned in the airlock. Disposable covers may be used in addition to dedicated shoes.
  • Section 9.2.3 page 11 “NOTE 2 After a garment has been tested for microbial contamination (se 4.4), it should not be worn in the APA until cleaned.”

SECTION 10 CLEANING AND DISINFECTION OF THE APA

Section 10.1 Disinfectants and cleaning agents

  • Section 10.1.2 page 11: “Only cleaning agents and disinfecting agents which are validated and approved shall be used.”
  • Section 10.1.6 page 11: “The removal of disinfectant and cleaning agent residues on product contact surfaces shall be verified.”

Section 10.2 Validation of disinfection procedures

  • Section 10.2.2 page 12: “Each facility shall have appropriate procedures in place to evaluate, approve and control the use of disinfectants.”

Section 10.3 Monitoring effectiveness of cleaning and disinfection

  • Section 10.3.3 page 12: “When unusual microbial results are encountered or persist, an investigation to identify the source of contamination shall be performed and documented.”

SECTION 12 MATERIALS AND EQUIPMENT DELIVERED TO ASEPTIC AREAS

Section 12.3 Bioburden

“The characterisation and resistance to inactivation of the bioburden on components and equipment that are introduced into the APA shall be periodically determined”.

SECTION 13 PROCESSING TIME

  • Section 13.1 page 13: “The compounding of bulk solutions shall be controlled in order to prevent potential increase in microbiological levels, and possibly endotoxins, that can occur up to the time that the bulk solutions are sterile filtered.”
  • Section 13.2 page 13: “The total time for the product filtration and filling operations, and holding time after filtration and prior to filling, shall be limited to a defined maximum.”

SECTION 14 ENVIRONMENTAL MONITORING PROGRAMMES

Section 14.2 Sampling

Section 14.2.1 Processing zones and frequency of sampling

  • Section 14.2.1.1 page 14: “Product contact and material contact sites…monitored during and/or immediately after completion of the filling operation.”
  • Section 14.2.1.3 page 14: “Other processing zones…monitored at a defined frequency based on classification of the zones and testing data.”
  • Section 14.2.1.5 page 14: “The frequency of such monitoring for different facilities shall be based on historical environmental monitoring data and the type of product and process.”

Section 14.2.2 Sampling sites

“Sampling sites should be derived from and consistent with those used during validation activities”

SECTION 14.3 MICROBIOLOGICAL ENVIRONMENTAL MONITORING PROGRAMME

Section 14.3.1 General

  • Section 14.3.1.1 page 14: “Periodic monitoring shall include methods for yeast, moulds and other microorganisms.”
  • Section 14.3.1.2 page 14: “Validated recovery methods and calibrated equipment shall be used.”
  • Section 14.3.1.4 page 14: “Additional microbial and particulate monitoring shall be performed following start-up of operations or following periods of extended shut-down or modifications to the facility.”

Section 14.3.3 Microbiological sampling techniques

“Air sampling, using a volumetric sampling method, and other sampling methods, e.g. settle plates, swabs and contact plates, shall be used as appropriate to evaluate the microbiological quality of zones within the APA.”

SECTION 15 ALERT AND ACTION LEVELS

Section 15.1 Development of alert and action levels

  • Page 15 “NOTE1 Alert and action levels…derived from…results obtained during the aseptic process validation. Historical data…may also be appropriate..”
  • Page 15 “NOTE 2 Often one level is appropriate…for critical processing zones.”
  • Page 15 “NOTE 3 Adjustments of…levels could be appropriate, based (on)…media fill re-evaluations and…monitoring data.”

Section 15.2 Review of Data

  • “…Results of all environmental monitoring…reviewed in a timely manner against the alert and action levels…”

Section 15.3 Environmental monitoring trend analysis

  • Section 15.3.1 page 15: “Environmental data shall be analysed for trends on a routine basis.”
  • Section 15.3.2 page 15: “An investigation shall be initiated when necessary as indicated by trend data.”

SECTION 16 INVESTIGATIONS AND REPORTS

  • Section 16.1.1 page 15: “Investigations shall be conducted for unusual circumstances, extended mechanical breakdowns, or when action levels are exceeded.”
  • Section 16.1.2 page 15: “Written investigation procedures shall be available and…include…data to be collected, extent of the problem, impact on product or environmental control, quarantine of the product, whether the environmental control has been attained, follow-up testing and notification of affected responsible personnel.”

Section 16.2 Investigation testing

  • “Investigation testing shall be designed to locate the source of the problem and demonstrate that the area, process or equipment is once again under control. Revalidation may be necessary based on the outcome of the investigation.”

Section 16.3 Investigation report

  • Section 16.3.1 page 16: “The investigation shall be documented…”
  • Section 16.3.2 page 16: “The report shall be written and approved by management..”

SECTION 17 MEDIA FILLS (PROCESS SIMULATION TESTS)

Section 17.2 Initial performance qualification

  • Section 17.2.1 page 16: “Performance qualification shall be conducted for each new aseptic filling line and for each new product/container configuration which has not been represented in a previous performance qualification.
  • Section 17.2.2 page 16: “Performance qualification…Representative criteria include: the actual product/container configuration…two products which bracket all others…products which have been deemed to be the worst case…”
  • Page 17: Initial performance qualification…acceptance criteria: minimum of 3 media fills. Alert level = one contaminated unit – investigate cause and conduct one additional run (and repeat it if it fails); Action level = two contaminated units in a single run, or one each in two runs – cease qualification, investigate cause, repeat initial qualification.

Section 17.3 Periodic performance qualification

  • Section 17.3.1 page 17: “Scheduled…requalifications…at least every six months for each product/container configuration and aseptic filling line.”
  • Section 17.3.3 page 17: “Product manufacturing may resume while the media-filled units are being incubated; however, product release shall not occur until acceptable media-fill data are obtained.”

Section 17.4 Repeat of initial performance qualification

  • Section 17.4.2 page 18: “An aseptic process of filling line shall be subject to repeat performance qualification studies when: an action level is exceeded…production lines have not been in operation for an extended period…there has been a significant change.”

Section 17.5 Media-fill procedures

  • Section 17.5.1 page 18: “Media fill trials shall be conducted on separate days, at different times during the normal working period.”
  • Section 17.5.2 page 18: “A list of permitted and proscribed intervention events…shall be available.”
  • Section 17.5.3 page 18: “Media fill trials shall be conducted…that include “worst-case” conditions…”
  • Periodic requalification – media-fill acceptance criteria: if <500 unit per batch – 3 media fills. If ³500– 1 media fill.  Alert level = one contaminated unit in any unit.  Investigate and repeat run (³3000 units in batch, repeat run if values in Table 3 of ISO (located on page 21) are exceeded).  Action level = two contaminated unit in a single run.  Cease requalification, investigate and repeat initial qualification. (³3000 units in batch, cease, investigate and repeat if values in Table 3 of ISO (located on page 21) are exceeded).

Section 17.6 Media selection and growth support

  • Section 17.6.1 page 19: “Verification of growth promotion media used in specific media-fill runs shall be conducted following the run.”
  • Section 17.6.2 page 19: “The incubation temperature shall be the same as that used for the media-filled units.”
  • Section 17.6.3 page 19: “The media selected for media-fill runs shall be capable of growing a wide spectrum of microorganisms and of supporting microbial recovery and growth of low numbers of microorganisms, i.e. 100 colony forming units (CFU)/unit or less.

Section 17.7 Incubation and inspection of media-filled units

  • Section 17.7.1 page 19: “Leaking or damaged media-fill evaluation units shall be removed, and a record made of such removal, following processing and prior to incubation of the media.”
  • Section 17.6.2 page 19: “Media-filled units shall be incubated for a minimum of 14 days.”
  • Section 17.6.3 page 19: “Incubation temperatures shall be appropriate for the specific growth requirements of microorganisms that are anticipated in the aseptic filling area.”
  • Section 17.7.4 page 19: “Media-filled units shall be stored or manipulated to allow contact of the media with all product contact surfaces in the unit.”
  • Section 17.7.5 page 19: “After…incubation period…media-filled containers…visually inspected for…microbial growth.”
  • Section 17.7.6 page 19: “Microorganisms present in…units shall be identified…”
  • “NOTE 1 Inspection of the units at an earlier time period (3d to 7d incubation) can be useful to gain a preliminary indication of the results.”
  • “NOTE 2 Media-filled units should be chronologically identified within the batch…”

Section 17.9 Contamination with media

“Contamination of the facility and equipment with media during the media-fill runs shall not compromise…the facility and equipment or the product…using the same facility and equipment.”

Section 17.10 Data required for media fills

“All media-fill runs shall be fully documented, and the following information…included…:

  1. date and time of media fill
  2. identification of filling room used
  3. container/closure type and size
  4. volume filled per container
  5. filling speed
  6. filter lot and catalogue number
  7. type of media filled
  8. number of units filled
  9. number of units rejected at inspection and reason
  10. number of units incubated
  11. number of units positive
  12. incubation time and temperature for each group of units incubated and whether any group of units is subjected to two different temperatures during the incubation
  13. procedures used to simulate any steps of a normal production fill, which might include, for example, mock freeze-drying or substitution of vial headspace gas
  14. microbiological monitoring data obtained during the media-fill set-up and run
  15. list of personnel who participated in the media-fill
  16. growth promotion results of the media removed from filled containers
  17. identification of the microorganisms from any positive units, and investigation of any contamination events observed during media fills
  18. management review
  19. length of time media was stored in holding tank prior to filtration
  20. length of time taken to fill all containers

Section 17.11 Media-fill runs exceeding action levels

Section 17.11.1 Investigation

  • Section 17.11.1.1 page 22: “When…action levels… exceeded… investigation… conducted and documented…”
  • Section 17.11.1.2 page 22: “…action levels…exceeded…prompt review of all appropriate records relating to aseptic production between the current media fill and the last successful one.

“The investigation should include, but not be limited to, consideration of the following:

  1. Microbial environmental monitoring data
  2. Particulate monitoring data
  3. Personnel monitoring data (finger impressions, etc)
  4. Sterilisation cycles for media, commodities and equipment
  5. HEPA filter evaluation
  6. Room air flow patterns and pressures
  7. Operator technique and training
  8. Unusual events that occurred during the media fill
  9. Storage conditions of sterile commodities
  10. Identification of contaminants as a clue to the source of the contamination
  11. Housekeeping procedures and training
  12. Calibration of sterilisation equipment
  13. Pre and post-filter integrity test data, and/or filter housing assembly
  14. Product and/or process defects, and/or limitation of inspectional processes; and
  15. Documented disqualification of samples for obvious reasons prior to final reading

SECTION 18 FINISHED-PRODUCT STERILITY TESTING

Section 18.1 General

  • Page 23: “Sterility testing of aseptically filled products shall be conducted for each batch or lot.”
  • Section 18.2.1 page 23: “Positive sterility-test results shall be evaluated and an investigation shall be initiated…”
  • Section 18.2.2 page 23: “A correlation assessment between types of microorganisms found in the manufacturing environment, sterility testing room, and isolated from failed sterility tests shall be conducted.”

Section 18.3 Sampling Plans

  • Section 18.3.1 page 23: “Sampling plans…developed to assure representation of the entire batch…”

SECTION 19 STEAM IN PLACE

Section 19.1 General

  • Section 19.1.1 page 23: “Equipment which cannot be sterilized in an autoclave…shall be steam sterilised in situ with a demonstrated process lethality of six logarithms reduction…”
  • Section 19.1.2 page 24: “In the absence of an automated SIP system, manual procedures shall be defined, adhered to, and documented.”

SECTION 20 PROCESS FILTRATION

Section 20.1 Filter and filter equipment evaluation programme

  • Section 20.1.1 page 24: “A documented filter evaluation programme shall be established prior to validation and acceptance of filters.”
    • “The shedding of media-migration characteristics of the filter should be evaluated based on the intended life of the filter.”
  • Section 20.1.2 page 24: “Product sterilizing filters shall be evaluated by an appropriate and defined challenge test, or evidence of product-specific data from the filter manufacturer shall be available.”
  • Section 20.1.3 page 24: “Absorption or adsorption the product by the filter shall be evaluated.”

Section 20.1.1 Biological Testing

  • “If any plastics are used as components of filters/filter systems, biological safety testing should be conducted on each plastic material.  Testing may be conducted on the total filter/filter system.  Filters should be evaluated for the presence of endotoxins.”

Section 20.4 Filtration in the filling line

  • Section 20.4.3 page 25: “The filter manufacturer’s lot number shall be included in batch manufacturing records.”

SECTION 21 FREEZE-DRYING

Section 21.4 Process Routing

  • ”Facility design related to location of equipment for filling, freeze-drying and sealing shall be such that transport of open product is kept to the minimum possible.”

SECTION 21.11 MICROBIOLOGICAL AND PARTICULATE ENVIRONMENTAL MONITORING

  • “A programme for microbiological monitoring of product transfer and freeze-drying shall be implemented.”

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