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Guideline (SOP) for risk based Environmental Monitoring (EM) in Non Sterile drug manufacturing facility. Regulatory standards for non-sterile product manufacture and environmental control have not been consistently established, however, EU GMP requires inhalants to be manufactured in an ISO 8 environment and compendia, such as USP <1111> Microbiological Examination of Nonsterile Products.

Procedure for Environmental Monitoring  – Non Sterile Facility

• Environmental Monitoring Program Requirements For Non-Sterile Product Manufacturing Facilities:

  • Regulatory standards for non-sterile product manufacture and environmental control / monitoring have not been consistently established,

• • However, EU GMP requires inhalants to be manufactured in an ISO 8 environment and compendia, such as USP <1111> Microbiological Examination of Nonsterile Products:

• • Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use, list specific organisms that are to be excluded from some non-sterile dosage forms.

• • These specific organisms may be present in the environment and the Environmental Monitoring (EM) program at specific sites shall include methods to recover and identify them based on the risk of product contamination from environmental conditions such as wet environments, exposure to botanical or animal derived raw materials, etc.

• • Rather than routine sampling, identifying the source of specified organisms in Environmental Monitoring (EM) samples may be incorporated into the investigation program for product samples that do not meet compendial requirements for specified “Objectionable” organisms such as those listed in USP <1111>.

• • Risk assessments shall be prepared for all sites manufacturing non- sterile products to assess potential for contamination of the product (see Attachment IV – Example of Risk Assessment Template Non-Sterile Products).

• • Risk assessments shall be based on route of administration, product stability, manufacturing system controls, product moisture content,

• • Whether ingredients are derived from microbial, plant or animal sources, and any other parameter that could impact product microbial attribute requirements in regulatory filings and official.

• • Monitoring for total particulates and viable air sampling are not required for non-classified manufacturing areas.

• • Where air samples are deemed necessary based on risk assessments, active air samplers, such as RCS type, or settling plates exposed for not more than four hours shall be acceptable.

• • Justification for sampling frequency, setting the alert and action levels, level of microbial identifications, selection of sampling sites and excursion investigation processes shall be risk based.

• • Semi-annual (each six months) monitoring to specifically quantify and identify yeasts and molds shall be performed on representative processing surfaces using contact plates (RODAC) filled with differential media,

• • Such as Sabouraud Dextrose Agar for yeast and molds, to assess adverse trends that could impact product.

• • If all organisms are identified on routine samples, then semi-annual monitoring is not required.

• • The ability of routine RODAC samples to recover yeast and mold shall be correlated with RODAC plates containing media specific for yeast and molds, g. Sabouraud Dextrose or Potato Dextrose Agar.

• • Written cleaning / sanitization programs shall be in place for each non- sterile manufacturing site.

• Critical Utility System for Environmental Monitoring for Sterile and Non-Sterile Product Manufacturing Sites:

  • Critical utility sampling and testing requirements are dependent on the products manufactured in the Differences for sterile product and non-sterile product facilities are defined herein.

• • Compressed Gases/Air:

  • Sample and test personnel shall be trained to perform respective duties, including training in aseptic gowning, aseptic area technique, if entering aseptic manufacturing areas to sample.

• • Compressed gases/air used in Sterile Manufacturing shall meet the same environmental criteria as the classified areas within which they are used.

• • These gas/air systems shall be qualified and periodically tested to ensure that total and viable particulate limits are not exceeded.

• • Compressed gases/air in direct contact with non-sterile product, such as granulators, shall be qualified and periodically tested to ensure that total and viable particulate limits are not exceeded.

• • Devices used for total particulate and viable sampling of compressed gases/air shall be specially designed to account for supply pressure and be calibrated and/or standardized and qualified for use.

• • Table 1 provides minimum requirements for Environmental Monitoring (EM) of compressed gases/air.

Table 1: Environmental Monitoring Frequency for Compressed Gases

• • Where microbial-retentive filters are used on compressed gases in Grade A/B aseptic fill areas (where gases are required to be sterile),

• • These filters are also subject to filter validation and shall be integrity tested before installation and when being replaced after use.

• • Water and Clean Steam Systems:

• • Each site shall have effective written procedures describing the frequency, sample sites, the volume of samples, sample and test apparatus flushing requirements, and gowning requirements for sampling and testing water and clean steam systems.

• • All personnel involved with sampling and testing shall be trained to the microbiology standard for aseptic technique prior to performing their duties.

• • Minimum requirements for Water and Clean Steam system sampling and testing are listed in Table 2 that was derived from PDA TR#13.

Note: Additional testing may be required by different Pharmacopoeia in different countries and shall be incorporated into the testing program, as appropriate.

Typical Water and Steam System Monitoring Frequencies and Levels*

*Additional testing may be required by different Pharmacopoeia in different countries and shall be incorporated into the testing program, as appropriate.

• DATA REPORTING – ALL MANUFACTURING FACILITIES (EXCEPT AS INDICATED):

• • Averaging Environmental Monitoring (EM) results from the same or multiple sites is not allowed.

• • All Environmental Monitoring (EM) data and analytical results shall be maintained in a secure and controlled manner in compliance with the current version of SOP- Good Documentation Practices (GDP).

• • Aseptic area Environmental Monitoring (EM) data shall be assessed as part of the batch record review process, e.g., verification that sample data were within action levels, or that any investigations were completed and concluded that there was no adverse impact on the batch.

• • Non-Sterile product release procedures shall include review of open Environmental Monitoring (EM) investigations to assure there is no adverse impact to products being released to market.

• • Environmental Monitoring results for airborne particulate and viable microorganisms, as well as surface viable microorganisms shall be recorded and graphically trended on a monthly basis

• • Periodic Environmental Monitoring (EM) trend reports shall be prepared Monthly for sterile manufacturing facilities and

• • At least quarterly for non-sterile manufacturing.

• • Environmental Monitoring (EM) trend reports must be prepared that include all actions triggered by

• • • Environmental data excursions,

• • • Including a listing of deviations,

• • • Investigations,

• • • CAPAs, and batches potentially

• • Submit the EM trend reports to site management,

• • Include comparison for the prior twelve-month in EM trend reports.

• • Annually prepare a report summarizing data from each sample site and comparison of microorganism isolates found over the year.

• • Adverse trends shall be noted and reported immediately to the Quality Unit.

• ADVERSE TRENDS AND EXCURSIONS FOR ALL FACILITIES :

• • Alert limits – Environmental Monitoring (EM):

• • Exceeding total particulate alert limit shall trigger resample to confirm.

• • If not confirmed, no further action is required.

• • If confirmed, investigation and corrective actions shall be implemented.

• • Exceeding microbiological alert limits shall trigger review of previous data from the surrounding area and the specific location to determine if there is an adverse trend.

• • Exceeding alert limits in more than one (1) location or two (2) consecutive samples at the same sample site shall be considered equivalent to exceeding an action limit.

• • Action limits – Environmental Monitoring (EM):

• • • Exceeding total particulate action level shall result in suspension of the aseptic process in order to perform investigation and corrective action and should trigger an immediate resampling.

• • • Disposition of open product and sterile materials on the line shall be assessed, as well as whether the area can be used during the course of the investigation.

• • • Exceeding microbiological action limits shall trigger investigation and assessment of product manufactured at the time of the

• • • The extent of investigation shall be consistent with the severity of the excursion and include an evaluation of trending data.

• • Appropriate corrective actions shall be implemented, as necessary, through the formal CAPA Program to prevent future deviations.

• MICROBIAL IDENTIFICATION FOR ALL FACILITIES:

• • Microbial identifications may be performed in-house or by approved contract laboratories.

• • The morphologically characterized bacterial colony is structurally differentiated by Gram’s staining (Gram-positive and Gram-negative).

• • The Fungal colony (Yeast/Molds) is structurally differentiated by fungal staining their morphological description alone is suitable for isolates obtained from unclassified sites in non-sterile facilities and from Classes C and D support areas that exceed the alert/action/permissible level.

• • Not every isolate  needs  to  be  characterized;  atypical colony/representative isolates of the same macroscopic morphology is sufficient.

• • Molds (Filamentous fungi) colonies on agar Petri-plates morphological look like

• • • Cottony,

• • • Fluffy,

• • • Powdery, and

• • • Granular with or without radial groove.

• • When the action level is exceeded in Grades C and D environments, isolates shall be identified to the genus level and,

• • When deemed necessary during the investigation, to species.

• • Identification to the species level shall be performed for all isolates from Grade A monitoring and when alert or action levels are exceeded in the Grade B environment.

• • Identification to species shall be performed for alert and action level isolates from-

• • • Excipient,

• • • Finished Product,

• • • Environmental,

• • • Compressed air/gases, and

• • • Water Samples.

• • Strain typing or molecular fingerprinting shall be performed for significant product contamination failure, such as media fills and sterility tests, and may assist in tracing contamination source during investigations.

• EM MEDIA PREPARATION AND TESTING – ALL FACILITIES:

• • Written procedures shall be established for a Quality Control Program to ensure suitability and stability of microbiological growth media.

• • Media sterility and growth promotion must be assessed for each lot of media received or prepared in-house prior to release for use.

• • Growth promotion of all powdered media shall be confirmed upon receipt prior to use once it has been prepared according to instructions and autoclaved.

• • The use of commercially prepared media is recommended for critical zones, as these will have sufficient packaging and irradiation to provide sterile materials for sampling in the critical zones.

• • For lower classified areas, commercially prepared or in-house prepared media may be

• • There shall be a program for quarantine and release of microbiological media, including rehydrated and sterilized powdered Media shall not be used until growth promotion challenges are acceptably completed and sterility testing, where applicable, has passed.

• ENVIRONMENTAL MONITORING FACILITY AND CHAMBER TEMPERATURE, HUMIDITY AND DIFFERENTIAL PRESSURE IN ALL FACILITIES:

• • Environmental Monitoring Requirements:

• • Alarms (alert / action limits) shall be established for automated monitoring systems, where available.

• • Where automated alarms are not available, manual readings shall be documented in approved logbooks for each parameter at a frequency that assures product remains within acceptable limits.

• • Documented justification for monitoring frequencies shall be risk

• • Response to alarms and out of limit conditions:

• • Each site shall develop written procedures for response to environmental alarms and out-of-limit conditions for, but not limited to:

• • • Temperature,

• • • Total particulates (Sterile product facilities),

• • • Differential pressure,

• • • Humidity and failure of HVAC systems,

• • • Laminar air flow hoods and for sterile product RABS and isolators.

• • These procedures shall include requirements for:

• • • Reaction to out-of-limit total particulate results in critical zones

• • • Steps for protection of exposed product and components.

• • • Placing equipment into a safe condition.

• • • Evacuation of personnel.

• • • Wait time for a purge of classified areas before resuming operation.

• • • Cleaning and sanitization.

• • • Steps for resuming operations when environmental conditions are restored to normal operating conditions.

• • Environmental conditions within refrigerators, freezers, incubators, and other environmental chambers shall be recorded using automated monitoring systems or chart recorders.

• • Monitoring systems shall include alarm capabilities.

• • Requirements for typical Compendial chambers are listed below:

• • Temperature limits:

• • • Refrigerators: 2°C – 8°C.
    • Freezers: -25°C to -10°C, typical, but maybe colder.

• • • Controlled Room Temperature: 20°C – 25°C with excursions allowed between 15°C and 30°C and MKT is not more than 25°C.

• • • Incubators 20°C – 25°C and 30°C – 35°C

• • Maximum time limits must be established for temperature or humidity excursions before material must be relocated to another qualified chamber.

• • Time limits shall be based on risk assessments.

• • Mean Kinetic Temperature (MKT) calculations may be used to assess impact on product and materials. Refer to USP <1079> for MKT

• • Humidity Limits in chambers:

• • Humidity limits vary by dosage form and product/material label

References – Environmental Monitoring (EM)

• • European Commission, EudraLex. The Rules Governing Medicinal Products in the European Union Volume 4. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 . Manufacture of Sterile Medicinal Products

• • FDA Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, September 2004

• • General Chapter USP <1111> Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use

• • General Chapter USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments

• • General Chapter USP <1117> Microbiological Best Laboratory Practices

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