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The manufacture of sterile pharmaceutical product requires specific care Regarding environment, premises and practice of the personnel. Regulations in place to be used by the Pharmaceutical Industry give requirements on the environmental monitoring program. With the publication of FDA Warning Letters and 483 That form shows environmental monitoring procedure and practice of the staff belong to top 10 of the gaps found During inspections.
This article, for the Environmental Monitoring program (EM) in aseptic processing as well in Conventional Clean Rooms (CCR) or using Isolator / RABS technology: Describes the main expectations of the règlements in place, presents the hot topics in microbiology and Gives solutions for implementation of best practices. From the gaps highlight highlighted by FDA During inspections, Microbiology The Following topics will be Described: samples rent justification, missing samples and data interpretation, trending system and CAPA system.
1. 1 Environmental Monitoring in CCR - Key Expectations
Regulations[(1)(2)(3)(4)(5)(6)(7)(8)] The Following key issues require to be Performed During The EM for filling operations in CCR:
- Filling in aseptic processing in Conventional Clean Room (CCR) should be classified Class ISO 5 (Grade A).
- Surrounding room should be classified ISO Class 5 (Grade B at rest).
- Surrounding room should be maintained ISO Class 7 (Grade B in operation).
- Environmental Monitoring Program (EM) should be in operation.
- EM locations should be based on a formal risk analysis and results.
- For CCR control of the staff is required Gloves / Garment depends on the room class.
- For CCR Active Air Sample (AAS), Passive Air Sample (PAS) & Surfaces Monitoring (SM) should be performed.
- Surfaces should be monitored after completion of the working operation
- Gloves of the staff should be monitored at each exit and after critical interventions
- Garment of staff (Grades A / B) should be monitored for each shift
- Limits for each sample type (Refer to EU / GMPs / Annex 1)
- Trending system using CRR (Refer to USP <1116>).
1.2. Environmental Monitoring using Isolator / closed RABS Technology - Key Expectations
Regulations [(1)(2)(3)(4)(5)(6)(7)(8)] The Following require key issues to be Performed During the EM for filling operations using closed RABS isolator or technologies:
- Isolator should be classified Class ISO 5 (Grade A).
- Surrounding room should be classified Class ISO 8 (C / D).
- Environmental Monitoring (EM) should be in operation.
- EM locations should be based on a formal and qualitative evaluation of the results obtained during the Qualification Program & Routine.
- For isolator control of the staff is not required.
- For isolator AAS, PAS & Surfaces should be performed.
- Surfaces should be monitored after completion of the filling operation or campaign.
- Critical gloves and half-suits should be monitored at the end of each filling operation.
- Limits for each sample type (Refer to EU / GMPs / Annex 1).
- Trending system using CRR (Refer to USP <1116>).
2. Hot Topics in Microbiology & Best Practices
2. Samples 1 rental Justification
Samples are Generally Described in the procedures for Environmental Monitoring program. Aim the exact location for Each is not always Clearly defined and / or Justified.
FDA Warning Letter 2011: "Your environmental monitoring program does not give assurance that environmental contaminants are reliably detected:
- Your practice of collecting samples from the gloves of operators is an acceptable one.
- Your SOP fails to include instructions for the location and duration of samples collected in the critical aseptic processing areas. "
What are the expectations of the autorités?
FDA - Guidance for Industry - Aseptic Processing - 2004:
- "A vigilant and responsive personal monitoring program should be established. Monitoring should be accomplished by obtaining surface samples Each operator's gloves were daily basis, Or in association with Each batch. This sampling by shoulds be accompagné Appropriate sampling frequency for year --other Strategically selected locations of the gown. The quality control unit shoulds ESTABLISH a more comprehensive monitoring program for operators Involved in operations are qui Especially labor intensive (ie, those requiring repeated or complex aseptic manipulations). "
- "We recommend that this assessment include microbiological sampling area of several locations were gown (eg, glove fingers, facemask, forearm, chest). Sampling locations shoulds be Justified. Following initial assessment of gowning year, periodic requalification will provide for the monitoring of various gowning locations over a period of time to ensure consistent acceptance of aseptic gowning techniques. "
- "The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come into contact with the product, container, and closures
- "Written procedures should include a list of locations to be sampled.«
- « sample timing, frequency, and Carefully rental shoulds be selected based upon Their relationship to the operation performed.«
- "Samples should be taken from the aseptic corridors, gowning rooms) using scientifically sound sampling procedures. "
- « Air and Surface samples shoulds be taken at the rentals where significant activity or product exposure occurs during production. "
- "Critical surfaces that come into contact with the sterile product should remain sterile throughout an operation. "
- "When Identifying critical locations to be sampled, Consideration shoulds be Given To the Points of contamination risk in a process, Factoring Including Such As difficulty of setup, length of processing time, and impact of interventions.«
- « All environmental monitoring locations shoulds be Described in SOPs with Sufficient detail to allow for reproducible sampling of a rental Given surveyed.«
- « Written SOPs shoulds aussi address Elements Such As frequency of sampling, samples are taken When the (Ie, During or at the finding of operations) Duration of sampling, sample size (eg, surface area, air volume), specific sampling equipment and techniques, alert and action levels, and appropriate response to deviations from alert or action levels. "
- « Surfaces - Environmental monitoring involves sampling various surfaces for microbiological quality. For example, product contacting surfaces, floors, walls, and equipment should be tested on a regular basis. "
- « Active Air Sampling - We recommend that these devices be used on each production shift to evaluate aseptic processing areas at Carefully Chosen rentals. "
- « Passive Air Sampling - Their value in critical areas will be enhanced by requiring that Positioned in flat rentals are posing the greatest risk of product contamination. »
ISO 13408 - Share 1:
"Gloved fingerprints of personnel present in the direct support area and / or critical processing area shall be monitored daily.
At defined intervals samples from the gowns aussi `shall be taken (eg Both forearms, chest, hood.
NOTE: The frequency of sampling of gowns and gloves is based on the nature of the performed. "
ISO 14698 - Share 1:
'The following are examples of elements to be considered: Choice of the sampling rental, taking account of the location and function of the risk zone. "
PDA / TR No. 13:
"The following should be taken into consideration when assessing the following:
1. Sites processes or microbial contamination in qui Would Most Likely effect one year-have adverse product quality
2. Sites That Would Most Likely Demonstrate the heaviest microbial proliferation During actual output
3. Whether the site selection shoulds Involve a statistical gold design shoulds be made on the basis of profiling grid
4. Whether routine monitoring websites shoulds be Rotated
5. Sites That Represent The Most unreachable or difficulty to clean and disinfect areas
6. Modes of microbes in the environment dispensal
7. Sampling at a site that may be disturbed by the product. "
- "Monitoring locations should be determined based on an assessment of risk. "
- « Regarded Rentals Those include shoulds in proximity of the exposed product, containers, closures, and product contacting surfaces.«
- "The user should conduct a Prospective risk analysis and Develop a rationale for the sampling locations and frequencies for each controlled environment. "
EC / GMPs / Annex 1:
"Clean rooms and clean air devices should be routinely monitored in operation the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and / or clean air devices. "
How to justify samples rent?
Apply a risk based approach for the analysis methodology-combining:
– Process knowledge and understanding Including holder with smoke test studies
- Evaluation of process criticality
– Critical Control Points (CCP) definition and location
– Sampling Plan program Description
The risk analysis evaluation approach should follow the following steps:
a / Identify the potential sources / causes of contamination:
- Ishikawa fishbone diagram (Figure 3),
- Smoke test studies,
- Data from the initial EM Qualification.
b / Risk assessment: Levels of Severity and Occurrence assessment tables and quotation For Each speech at risk.
c / Mapping of potential sources / causes of contamination with risk assessment process For Each operation: Critical Control Points (CCPs) approach & Total environmental risk assessment.
Figures 4, 5 6 & describe an example of definition of the sample locations from year aseptic filling process Including closure of vials with rubber stoppers.
(Figure 4 describes an aseptic filling process in CCR with the following flows:- Product to be filled- Primary packaging components (sterile & pyrogen free vials after direct transfer from the oven)- Stoppering components after transfer by the personnel from sterile bags.
(Figure 5 1 foot dimension (FDA requirement) is a feature of the field where it is located in the airflow, and during filling / closing operations and their respective areas in the perimeter of intervention.e personl (orange triangles).
All Critical Control Points (CCPs) are defined as full red spots.
(Figure 6 Description of the samples for all samples (Active Air Sampling using an impaction system, Passive Air Sampling using 90mm, Surface Monitoring using contact plates 25cm2).
2.2. Missing Samples
FDA - Warning Letter 2011: "Your firm has not thoroughly
investigate any unexplained discrepancies, for example for missing environmental samples. "
FDA - Warning Letter 2012: "Approximately 846 EM samples were not collected in the grades A & C areas from March 2010 to Feb 2012.
This substantial number of missed samples suggests that you are concerned about your environmental program. Collecting scheduled EM samples is critical of any environmental control program at an aseptic manufacturing facility. "
What is the expectation of the autorités?
FDA: Missing samples is a deviation.
What to do?
If time immediately Concerned:
- This incident must be managed as a deviation involving the performance of an investigation.
- Evaluate the impact of the batch.
- In grades C & D the impact should be low. But in A & B grades surround the impact is high up to batch destruction.
- Review of the other results and trend at the same location on a period of time.
- Review of the results of the other rental the day of the missing sample.
If the origin is a damage of the plate, a solution could be incubation of this plate with an information of the risk to contamination of this damage. If important growth in the future of the trend, evaluate after investigation the possibility for invalidation.
A CAPA must be defined and scheduled for action for traceability of all samples and the possibility to know the status of each sample at each critical step such as sampling, transfer, incubation, reading (Refer to Figure 7).
It's essential to keep and manage all the traceability of the sampling program from the initial step (preparation of samples devices), the incubation operations, to the final step (results and data interpretation)
Figure 7 Gives an example of the management of the samples Including the use of a tablet PC and a bar code scanning system.
2.3. Data Interpretation - Trending System & CAPA
Interpretation of the EM results shoulds be Described in a procedure intended Reach arent always easy to evaluate-.
Health Canada - 2012: "The approach to EM is not necessarily important enough to identify localized trends. "
What are the expectations of the autorités?
ISO 14698 - Share 1:
'To assist in interpretation, `shall be reviewed results over extended Periods to determine trends. The results of this study are based on the results of the investigations and their results. "
ISO 14698 - Share 2:
Management of microbiological results from risk areas should take the following factors into account: ...;
- trend analysis; ... »
"Data coming from a single sample are often not significant; Further, microbiological monitoring techniques may have serious shortcomings that result in a high degree of variability. Therefore, a graphic presentation of the results may be useful, but it may be useful in this context, or in the case of a significant change of occurrence, even though the results fall within the specified limits. "
ISO 13408 - Share 1:
"Environmental data (both counts and type of microbial isolates) shall be Analyzed for trends was routine basis. "
" AT trend report giving year overview of all environmental observations and trends. "
« Trend deferrals should include data generated by location, shift, room, gold --other operator parameters. When indicated by individual excursions and / or trend data, an investigation shall be initiated. "
« Examples of trends leading to an investigation include:
a) A trend Towards Higher numbers of microorganisms at a sampling site;
b) Repeated occurrence of microorganisms not often encountered. "
FDA / G for I / Aseptic Proc / 2004.:
Because false negatives can Occur, consecutive growth results are only one kind of adverse trend. Increased incidence of contamination over a period Given is an equal or more significant trend to be tracked. In the lack of Any adverse trend has single year result Above Action Level shoulds trigger an assessment and a determination about whether remedial Measures May be considers. In all room classes, remedial Measures shoulds be taken in response to unfavorable trends. The quality control unit shoulds Provide routine oversight of near-term (eg, daily, weekly, monthly, quarterly) and long-term trends in environmental and personal monitoring data. «
« Trend deferrals should include data generated by location, shift, room, operator, or --other parameters«
"The quality control unit should be responsible for the production of specialized data reports (eg, a search for a particular isolate over a year period) with the goal of investigating results beyond established levels and identifying any appropriate follow-up actions. Significant exchange in microbial flora should be considered in the review of the ongoing environmental monitoring data. "
PDA / TR No. 13:
"Routine review and analysis of environmental monitoring data for trends at an Appropriate frequency is essential to aid in the interpretation of process stability and environmental control for Assessment overall performance. "
"Recovery rate can be used for the generalization of the microbial load in the environment, equipment surfaces, material, and garment (Refer to USP <1116>). "
"The recommended recovery rate for ISO 5 environments can be achieved; ... »
"It is recommended that these companies develop their own recovery rate criteria for ISO 6, 7, and 8. "
"The analysis of contamination trends in an aseptic environment has long been a component of the environmental control program. "
"Because of the inherent variability of microbial sampling methods, contamination recovery rates are a more important measure of success. "
Table Describing contamination recovery rates for aseptic processes.
"Trend Analysis: Data from a microbial environmental monitoring program that can be related to time, shift, facility, and so on.
This information is periodically evaluated to ascertain whether it is under adequate control. A trend analysis is used to facilitate decision-making for requalification of a controlled environment or for maintenance and sanitization schedules. "
How to build a trend analysis system Considering the severity and the occurrence of the microbial contamination in the objective to evaluate-ict risk fo the process, the product, the patient?
Written procedures shoulds be ESTABLISHED, detailing frequency data review and action to be taken. The quality control unit shoulds Provide routine oversight of near-term (eg, daily, weekly, monthly, quarterly) and long-term trends in environmental and personal monitoring data.
Because of the limited accuracy and precision of assays microbial growth and recovery, analysts can Consider the frequency with qui contamination is detected Rather than absolute numbers of cfu detected in Any single sample. Contamination Implementation of the Recovery Rate (CRR) based on the Following
Number of results with positive growth
CRR = ____________________________________
Total number of samples
The objective of Each user shoulds be SRRB to use to track performance and to Ongoing refine the microbiological control program to foster improvement.
Action shoulds be required When the CRR trends above-the recommendations (USP <1116>) for a significant time.
May include corrective and preventive action are not limited to purpose The Following:
- Review the sanitization program, including cleaning procedures, application methods, and
- Reinforcement of personnel training
- Increased surveillance of personal practices
- Review of microbiological sampling methods, techniques, frequency, number of samples.
When higher-than-typical recovery levels are considered, additional action should be determined.
As a concluding regulation Does not always detail all requirements for Environmental Monitoring Program. Nevertheless whatever the driving box Each individual must be in place Justified When possible, supported by a risk based approach.
When "hot topics" in Microbiology emerge from inspections of return from autorités gold / During and self-inspection, it shoulds be a good opportunity to evaluate-the local performance for a challenge to access to "best practices".
Benoit RAMOND - SANOFI
(1) European Community - EudraLex - The Rules Governing Medicinal Products in the European Union, Volume 4 - Guidelines for Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 1 - Manufacture of Sterile Medicinal Products.
(2) FDA - Guidance for industry - Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practices - September 2004.
(3) USP <1116> - Microbiological Control and Monitoring of Aseptic Processing Environments.
(4) ISO 14644-1 - Cleanrooms and associated controlled environments - Part 1: Classification of air cleanliness
(5) ISO 14698-1 - Cleanrooms and associated controlled environments Biocontamination control - Part 1: General principles and methods.
(6) ISO 14698-2 - Cleanrooms and associated controlled environments - Part 2: Evaluation and interpretation of biocontamination data.
(7) 13408-1 - Aseptic Processing of Health Care Products - Part 1: General requirements.
(8) PDA - TR # 13 (Revised) - Fundamentals of an Environmental Monitoring Program - 2014.