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Environmental Monitoring – How to Satisfy the Regulator

Presented by Tanja Varglien, July 2017

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PIC/S Code of GMP Regulatory Requirements

• The PIC/S Guide to GMP requires that

• Clause 3.3 – Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture or storage

• Clause 5.10 - Products and materials should be protected from microbial and other contamination.

• Annex 1 Clause 8 – Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices

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PIC/S Code of GMP Regulatory Requirements (PE 009-13)

• Annex 3, Clause 19 – Workstations and their environment should be monitored with respect to radioactivity, particulate and microbiological quality as established during performance qualification (PQ)

• Part II, Clause 18.15 – Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems)

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General Requirements for Viable Environmental Monitoring – Annex 1

• Clause 18

• Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates)

• Sampling methods used in operation should not interfere with zone protection

• Results from monitoring should be considered when reviewing batch documentation for finished product release

• Surfaces and personnel should be monitored after critical operations

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General Requirements for Viable Environmental Monitoring – Annex 1

• Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation.

• Clause 19 - Recommended limits for microbiological monitoring of clean areas during operation

• Clause 20 - Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective actions

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Viable Environmental Monitoring

• Environmental monitoring is a tool utilised to evaluate the effectiveness of controls on the manufacturing environment. These controls include:

• Layout of the facility

• Process and personnel flows

• HVAC design

• Monitoring and maintenance

• Facility and equipment cleaning and sanitization/disinfection programs

• Facility environmental monitoring data is used to assess the current and continued effectiveness of the cleaning and sanitisation agents and procedures.

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Viable Environmental Monitoring Program

• The environmental monitoring program should be designed and implemented based on sound scientific principles

• The frequency, location and number of monitoring locations should be based on a formal risk assessment e.g.

• Product contact pathways, product exposure

• Personnel flows

• Hard to access or difficult to clean areas – “worse-case”

• Monitoring locations should be defined and documented e.g. procedure, maps, photos

• The frequency and level of monitoring should be defined e.g. every shift, daily, weekly, monthly

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Monitoring Methods

• A variety of monitoring methods may be utilised e.g.

• Passive air sampling e.g. settle plates

• Active air sampling e.g. Centifugal, filtration, STA

• Surface monitoring e.g. swabs, contact plates (RODAC)

• For settle plates, the maximum time settle plates can be exposed should be validated and defined. Plates can dessicate if left exposed for too long a period.

• Annex 15, Clause 9.3 – Where microbial testing of surfaces in clean rooms is carried out, validation should be performed on the test method to confirm that sanitising agents do not influence the recovery of microorganisms

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Monitoring Methods

• Procedures should describe how samples are taken and processed e.g.

• For swabbing, a 10cm x 10cm area is swabbed; rotate the swab during sampling.

• Sanitation of media into the filling room

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Monitoring Media

• Clause 6.25 – The in-use shelf life of microbiological media should be established, documented and scientifically justified.

• Clause 6.19 - Special attention should be given to the quality of laboratory reagents, volumetric glassware and solutions, reference standards and culture media. They should be prepared in accordance with written procedures.

• Clause 6.20 – Laboratory reagents, solutions, reference standards and culture media should be marked with the preparation and opening date and the signature of the person who prepared them. The expiry date of reagents and culture media should be indicated on the label, together with storage conditions.

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Monitoring Media

• Neutralizers should be added to media to inactivate surfaces treated with chemical disinfectants

• Are there procedures in place for the preparation, QC, release and storage of media ?

• Is the media made in-house or purchased ready made ?

• If made in-house, ensure the following records are available

• Control and traceability of starting materials

• Sterilization records

• Quality control records e.g. growth promotion, sterility

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Monitoring Media

• If purchased ready made, ensure the following records are available

• Certificate of Analysis

• Results of QC testing (as applicable)

• Supplier qualification records (as applicable)

• Validated process (sanitation) for transferring media and equipment to aseptic filling rooms

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Incubation conditions

• Manufacturers should select appropriate media and incubation regimes.

• For general (TSA) media, media is usually incubated at

30 - 35°C for 3 – 5 days

• For fungi, media is usually incubated at room temperature (20 - 25°C for 5 – 7 days)

• A combination regime may be appropriate

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Monitoring Limits

• Action limits are generally based on any applicable regulatory requirements (Annex 1)

• Alert limits are generally driven by a review of historical data or commensurate with the activities being performed.

• If these limits are exceeded, procedures should prescribe corrective actions

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Remedial Actions to be taken in the Event of Out-of-Limit and Out-of-Trend Results

• Procedures should define actions to be taken when OOL excursions or adverse trends occur, e.g.

• Raise an NCR, OOS

• Initiate an investigation including root cause analysis, QRM, review of unusual events

• Remedial actions – e.g. additional cleaning and sanitation

• Follow-up monitoring – routine or increased level

• Review impact of result on previously filled batches

• Verification of effectiveness of any actions taken

• Need to fill a process simulation batch

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Qualification of Equipment

• Laboratory equipment e.g. incubators, active air samplers, plate counters, autoclaves should be appropriately qualified, timers

• Incubators should be monitored, ideally continuously with dataloggers or linked to a BMS.

• Procedures should define actions to be taken when there are excursions

• There should be schedules and records for calibration and preventative maintenance activities

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Review and Analysis of Data

• Clause 6.9 – Some kinds of data (e.g. test results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any Out of Trend or Out of Specification data should be addressed and subject to investigation.

• Routine review and analysis of environmental monitoring data is essential to aid in the interpretation of process stability and assess overall control performance.

• Results should be trended and subject to management review (Clause 1.6)

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Review and Analysis of Data

• Monitoring trend reports typically generated quarterly and/or yearly (minimum)

• Alert and Action limits should be reviewed as part of routine trend analysis. They may be revised to reflect improvements, advances in technology, changes in use patterns, or other changes

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Operator (Gowning) Qualification

• Personnel required to work in an aseptic environment are required to be trained and certified to properly gown via a gowning certification process.

• Gowning certification may include additional monitoring sites beyond those routinely monitored e.g. the forehead, mask, neck, forearm, wrists, shoulders, finger impressions, chest, garment zipper.

• Acceptance criteria – x3 consecutive satisfactory results

• Bi-annual or yearly gowning re-certification (x1) should occur.

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Operator (Gowning) Qualification

• Action limits are generally based on any applicable regulatory requirements (Annex 1). Alert limits are driven by a review of historical data or commensurate with the activities being performed.

• Procedures should define actions to be taken if results exceed the Action level e.g.

• Retraining and/or recertification

• Restrict operator access to the aseptic filling room

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Routine Personnel Monitoring

• Routine monitoring should include finger impressions from both hands e.g.

• Each time an operator exits a filling room

• After critical operations e.g. aseptic set up of the filling machine.

• After maintenance activities

• Consideration should also be given to monitoring garments e.g. chest, forearms and/or wrists, at a defined frequency

• Operators should be instructed not to sanitise their gloves immediately before prints are taken

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Routine Personnel Monitoring

• Action limits are generally based on applicable regulatory requirements (Annex 1).

• For RABS, an Action limit of NMT 5cfu (Grade B) may be acceptable in operation however, different limits would be required for samples taken at the end of aseptic set up of the filling machine.

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Identification of Isolates

• The manufacturer should have a system for the identification of microorganisms. This may be occur in-house or by the use of external contract laboratories

• Automated methods are either phenotypic or genotypic methods. Identification by genotypic method is required is identification is required to invalidate a sterility test positive

• The frequency and level of identification should be defined in a procedure e.g.

• All microorganisms isolated from Grade A & B areas are speciated.

• All microorganisms isolated from Grade C & D areas identified to genus level

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Non-sterile and Complementary Medicines

• For non-sterile and complementary medicines, the requirements for viable environmental monitoring are not as clear or defined. For these products, risk management principles should be used to determine the microbial quality of the environment commensurate with the products manufactured within

• Monitoring frequency typically every 3 or 6 months.

• Monitoring methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates) are acceptable

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Non-sterile and Complementary Medicines

• Alert and Action limits must be defined. Should be based on historical data; typically based on Annex 1, Grade D limits

• Actions to be taken in the event of OOL excursions are often poorly defined e.g.

• Identification of microorganism isolated

• Cleaning and sanitation

• Follow up monitoring

• Trending of data is expected

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Recap?

There are regulations which mandate how an environmental monitoring program is designed

The environmental monitoring program should be designed and implemented based on sound scientific principles.

Regulatory inspectors are individuals with specific areas of interest and expectations

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Thank you for your time.Questions?

Tanja Varglien

tanja.varglien@pharmout.net

Lead Consultant

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