Best Practice in Environmental Monitoring

Transcription

1 Best Practice in Environmental Monitoring Annette Grundy July

2 Acknowledgement Dr Ed Tidswell previous roles at Baxter Senior Director R&D and Quality Director USP expert committee member Ed was the global leader for the overall strategy and US leader for the implementation of this process within Baxter 2

3 Goal of program Drive improved compliance and continuous improvement Provide site/plant flexibility to drive efficiency improvements Simplified risk based approach utilizing existing programs Quality Quotient EMS (Enterprise Management Systems) RBLCM (Risk Based Life Cycle Management) 3

4 What is System-Based Microbial Control? System A set of things working together as parts of a mechanism or an interconnecting network; a complex whole: Logic The principles and reasoning permitting sound decision making 4

5 What is System-Based Microbial Control? A systematic and data driven management process for the identification and control of microbial hazards during the drug and device manufacturing life-cycle; assuring products that are safe and efficacious A self-detecting, self-correcting system Systems thinking is not one thing, but a set of habits or practices A framework that is based on the recognition that the component parts of a system are best understood in relationships to each other rather than in isolation 5

6 Why System-Based Microbial Control? Increased Flexibility & Compliance Patient safety is based upon clear understanding of risk and performance. Without documented logic decision becomes arbitrary and compliance driven by strict adherence to rules, reducing flexibility, patient safety and increasing costs Enhances & Grows Competency Focuses on facts, data and underpinning science and engineering. Drives evaluation of data and controls from all elements of quality assurance, cohesively geared to patient safety 6

7 Why System-Based Microbial Control? Self-Detecting Self-Correcting Systems Sustained continuous improvement, preventative corrections and improved process control require systems that self-detect and selfcorrect Improved Process Control Improved process control increases process and product performance, drives efficiency and process optimization, reduces scrap/conversion loss and FCAs 7

8 Microbial Monitoring & Control Oldfashioned approach Built from add-on specific requirements or instructions (Ad Hoc) Not well documented or easily understood logic for the selection of controls and monitoring Costly due to excessive or poorly targeted testing, controls and monitoring Difficult to change through inability to predict, detect and correct Uncertain control of product quality Does not permit flexible self-determined patient safety compliance 8

9 System-Based Microbial Control Systematic construction of controls Designed on easily understandable and documented logic of controls and monitoring Efficient through value-adding testing and controls Easier to change through increased predictability, self-detection and self-correction Certain control of product quality assurance Permits flexible self-determined patient safety compliance Takes the microbiologist out of the lab and into the process 9

10 n addition to more flexibility, new approach rives more robust improvement plans Process flow & essential requirements Risk assessments Control scheme Quality plan EMPQ Signal analysis Sampling plan Investigations 10

11 Reviewing process flow and essential requirements helps establish critical points for risk assessments Process flow & essential requirements Risk assessments Control scheme Quality plan EMPQ Process flow and essential requirements established through RBLCM or existing pfmeas Signal analysis When building a microbial control scheme, consider entire process flow Include full list of risks to be evaluated through risk assessments Investigations Sampling plan 11

12 Risk assessments Process flow & essential requirements Risk assessments Control scheme Quality plan EMPQ Risk assessments should evaluate the severity and probability of failure modes occurring They should consider all elements of the production process, Signal including analysis traffic flow, Sampling product plan movement, etc. Output should be a categorized list of the highest risk activities/areas within the controlled environment that inform where and how we monitor and control Investigations our environment 12

13 Control scheme Process flow & essential requirements Risk assessments Control scheme Quality plan EMPQ The control scheme should summarize how all of the risks identified through risk assessments are controlled to acceptable levels It should include all types of control including Signal analysis Sampling plan design elements (e.g. airlocks, HEPA filters), training, personnel monitoring, sampling, cleaning cycles, etc. Investigations 13

14 Quality plan Process flow & essential requirements Risk assessments Control scheme Quality plan EMPQ The quality plan documents any improvement opportunities for the routine control of the controlled environment Signal analysis These should be Sampling identified plan through the initial risk assessment, as well as on-going trending and investigations Investigations 14

15 EMPQ Process flow & essential requirements Risk assessments Control scheme Quality plan An environmental monitoring performance qualification must be run to validate the proposed control scheme It must demonstrate through samples that we maintain Signal a analysis state of control in our controlled environment by following all elements of the control plan Investigations EMPQ Sampling plan 15

16 Sampling plan Process flow & essential requirements Risk assessments Control scheme Quality plan A routine sampling plan should be developed that includes the critical testing points identified in the control scheme and is verified through EMPQ The sampling plan should Signal analysis outline the number, type, and frequency for all surface, air, personnel, and product tests which occur during the defined process flow Investigations EMPQ Sampling plan 16

17 Data collection and trending Process flow & essential requirements Risk assessments Control scheme Quality plan Signal analysis Investigations The EMPQ results of all routine sampling should be tracked in LIMS, Excel, or another electronic database tool Sampling Results plan should be reviewed to observe any negative trends Results should also inform future control schemes and sampling plans as they are updated 17

18 Investigations Process flow & essential requirements Risk assessments Control scheme Quality plan Signal analysis Investigations Investigations should seek to uncover the root cause of any activity or result outside the normal EMPQ state of control If the root cause is a known issue, the investigation should be close-referenced to the Sampling relevant plan item on the quality plan If the root cause represents a true non-conformance, use the QMS and update the Quality plan 18

19 Risk Assessments pfmea Microbial Ingress assessment of probability and severity of microbial ingress in to the process Microbial Proliferation assessment of probability and severity of microorganisms replicating at that point in the process Microbial Retention assessment of probability and severity of microorganisms remaining, staying, adhering to that part of the process 19

20 Risk Assessments Traffic Flow & Touch Points Personnel Product Waste Components External to Area - Consider traffic flow outside the immediate areas where common touch points can occur from items that never enter the cleanroom or environment under evaluation 20

21 Quantitative Risk Assessments Air-borne ingress for open process steps or open containers air borne ingress can be quantified Mechanics of air flow air flows and contamination rates are quantifiable as likely units contaminated with at least 1 cfu QbD quantitative assessment of contamination risk maps design space in a surface response model permitting QbD principles to be applied Probability of Ingress Magnitude of Challenge (cfu) Time of Exposure 21

22 Real Time Risk Assessments Behavior, operationally focused tool Structured, objective assessment of cleanroom microbiological risks Regularly executed during shifts (in real-time) Performed and overseen by Microbiologists Identified risks mitigated at time of discovery (real-time) Risks are reported to Manufacturing, Quality, Engineering management Focus alters with improved performance - evergreen Continuous improvement on cgmp Microbiologist Manufacturing Engineers 22

23 Key Points Triggers Triggers Set to avoid nuisance or noise responses Recovery rates and hit rates Define risk profile or minimum species profile and index microorganisms to respond to Inspection, audit observations Control fails (e.g. growth promotion) 23

24 Example Triggers Main Categories of Microorganism Recovered From Cleanrooms* Microorganism Grade B Grade C Grade D Gram positive 81% 63% 41% cocci Gram positive non-sporing rods Gram positive sporing rods Gram negative rods Fungi, yeasts, mold 3% 14% 12% 13% 10% 19% 2% 12% 20% 1% 1% 8% Aseptic Manufacturing Cleanroom Recovery Rates** Room Classification Active Viable Air (%) Passive Viable Air (%) Surface Sample (%) Glove or Garment (%) Isolator/Closed RABS < 0.1 < 0.1 < 0.1 < 0.1 (ISO 5 or better) Grade B < 1 < 1 < 1 < 1 Grade C < 5 < 5 < 5 < 5 Grade D < 10 < 10 < 10 < 10 *Derived from Sandal, T. (2011). A Review of Cleanroom Microflora: Types, Trends, and Patterns., PDA J. Pharm. Sci and Tech., 65, ** USP <1116> 24

25 APAC Quality Sharepoint: Data Entry Create a new data entry or view the data entry screen. 25

26 APAC Quality Sharepoint: Data Entry Form 26

27 APAC Quality Sharepoint: Select Graph/Metrics for viewing Select appropriate graph from the drop down. 27

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29 Key Points Actions Risk assessment review root cause or failure mode included? If root cause or failure mode included was it risk assessed appropriately? Re-assess with improved knowledge If risk assessment was appropriate were the controls adequate? Adjust, amend, add as necessary and include in Quality Plan Review control plan were the cohesive controls and monitoring program appropriate? Adjust, change as necessary Control Plan Review qualifications (environmental monitoring performance qualification). Adjust, add as necessary and include on Quality Plan Actions instill continued improvement in know-how, competency, knowledge and keeps the system evergreen 29

30 Key Points Control Plan Describes holistic microbiological controls, and monitoring Rationale for cohesive set of controls and monitoring Single source document for risk-based microbial controls States the logic, science and engineering rationale knowledge management Permits a holistic view of cohesive controls Can be used to change sampling and controls A swift and easy means for non-facility personnel to evaluate the health of the facility Reviewed upon triggers and therefore assists continued improvement in know-how, competency, knowledge and keeps the system evergreen 30

31 Key Points Quality Plan Describes environmental control improvements Cohesive holistic plan and schedule of actions and improvements States the logic and rationale for the sequence and schedule Includes bridging actions Maintained evergreen to sustain a genuinely continuum of systematic and cohesive improvements Regularly reviewed and approved by Quality and manufacturing 31

32 Why System-Based Microbial Control? Challenges Supply/shortage Regulations and standards are complex New processes, new technologies, new products Needs Agility, flexibility, speed. Commensurate compliance, global integration. Systems thinking with improved know-how 32

33 Benefits of System-Based Microbial Control Structured approach Uses risk based approach and sound science Engineering foundation and risk understanding drives better patient safety Drives continuous improvement and efficiency Drives improved understanding of microbiological principles and competency across workforce Documents current state and provides clear logic of road map for the future state drives the aspiration to improve 33

34 ANY QUESTIONS? Click to add text, or delete box 34