Best Practice in Environmental Monitoring...Process flow & essential requirements Risk assessments Control scheme Quality plan EMPQ Signal analysis Sampling plan Investigations •Risk

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Best Practice in

Environmental

MonitoringAnnette Grundy

July 12 2016

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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

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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)

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What is System-Based Microbial Control?

•Logic – The principles

and reasoning

permitting sound

decision making

•System – A set of things

working together as parts of a mechanism or an interconnecting network; a complex whole:

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What is System-Based Microbial Control?

• A systematic and data driven management process for theidentification and control of microbial hazards during the drug anddevice manufacturing life-cycle; assuring products that are safe andefficacious

• 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 componentparts of a system are best understood in relationships to eachother rather than in isolation

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Why System-Based Microbial Control?

Increased Flexibility & CompliancePatient safety is based upon clear understanding of risk andperformance. Without documented logic decision becomes arbitraryand compliance driven by strict adherence to rules, reducing flexibility,patient safety and increasing costs

Enhances & Grows CompetencyFocuses on facts, data and underpinning science and engineering.Drives evaluation of data and controls from all elements of qualityassurance, cohesively geared to patient safety

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Self-Detecting Self-Correcting SystemsSustained continuous improvement, preventative corrections andimproved process control require systems that self-detect and self-correct

Improved Process ControlImproved process control increases process and product performance,drives efficiency and process optimization, reduces scrap/conversionloss and FCAs

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Microbial Monitoring & Control – ‘Old-

fashioned’ 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

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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

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In addition to more flexibility, new approach drives more robust improvement plans

Process flow & essential

requirementsRisk assessments Control scheme Quality plan

EMPQ

Sampling planSignal analysis

Investigations

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Reviewing process flow and essential requirements helps establish critical points for risk assessmentsProcess flow &

essential requirements

Risk assessments Control scheme Quality plan

EMPQ


Investigations

• Process flow and essential requirements established through RBLCM or existing pFMEAs

•When building a microbial control scheme, consider entire process flow

• Include full list of risks to be evaluated through risk assessments

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Risk assessments



EMPQ


Investigations

• Risk assessments should evaluate the severity and probability of failure modes occurring

• They should consider all elements of the production process, including traffic flow, product 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 our environment

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Control scheme



EMPQ


Investigations

• 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 design elements (e.g. airlocks, HEPA filters), training, personnel monitoring, sampling, cleaning cycles, etc.

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Quality plan



EMPQ


Investigations

• The quality plan documents any improvement opportunities for the routine control of the controlled environment

• These should be identified through the initial risk assessment, as well as on-going trending and investigations

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EMPQ



EMPQ


Investigations

• An environmental monitoring performance qualification must be run to validate the proposed control scheme

• It must demonstrate through samples that we maintain a state of control in our controlled environment by following all elements of the control plan

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Sampling plan



EMPQ


Investigations

• 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 outline the number, type, and frequency for all surface, air, personnel, and product tests which occur during the defined process flow

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Data collection and trending



EMPQ


Investigations

• The results of all routine sampling should be tracked in LIMS, Excel, or another electronic database tool

• Results should be reviewed to observe any negative trends

• Results should also inform future control schemes and sampling plans as they are updated

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Investigations



EMPQ


Investigations

• Investigations should seek to uncover the root cause of any activity or result outside the normal state of control

• If the root cause is a known issue, the investigation should be close-referenced to the relevant item on the quality plan

• If the root cause represents a true non-conformance, use the QMS and update the Quality plan

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Risk Assessments – pFMEA

Microbial Ingress –

assessment of probability and

severity of microbial ingress in to

the process

Microbial Proliferation –


severity of microorganisms

replicating at that point in the

process

Microbial Retention –


severity of microorganisms

remaining, staying, adhering to

that part of the process

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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

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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

Time of

Exposure

Magnitude of Challenge (cfu)

Probability of Ingress

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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

Engineers

Manufacturing

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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)

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Example Triggers

Microorganism Grade B Grade CGrade D

Gram positive cocci

81% 63% 41%

Gram positive non-sporing rods

3% 14% 12%

Gram positive sporing rods

13% 10% 19%

Gram negative rods

2% 12% 20%

Fungi, yeasts, mold

1% 1% 8%

*Derived from Sandal, T. (2011). A Review of Cleanroom Microflora: Types, Trends, and Patterns.,

PDA J. Pharm. Sci and Tech., 65, 392-403.

** USP <1116>

Main Categories of Microorganism

Recovered From Cleanrooms*

Room Classification

Active Viable

Air (%)

Passive Viable

Air (%)

Surface Sample

(%)

Glove or Garment

(%)

Isolator/Closed RABS

(ISO 5 or better)< 0.1 < 0.1 < 0.1 < 0.1

Grade B < 1 < 1 < 1 < 1

Grade C < 5 < 5 < 5 < 5

Grade D < 10 < 10 < 10 < 10

Aseptic Manufacturing Cleanroom

Recovery Rates**

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APAC Quality Sharepoint: Data Entry

Create a new data entry or view the data entry screen.

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APAC Quality Sharepoint: Data Entry Form

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APAC Quality Sharepoint: Select Graph/Metrics for viewing

Select appropriate graph from the drop down.

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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’

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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’

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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

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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

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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

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ANY QUESTIONS?

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