Control and Contamination

Company Confidential

PDA Midwest 13th Annual Microbial Control and Contamination

Cleanroom Validation – Disinfection and Environmental Monitoring

September 22, 2021

Joe McCall, SM (NRCM)

Director, QA Technical Services

ADMA Biologics

Company Confidential2

Cleanroom Qualification / Validation

Agenda:

Regulatory Perspectives

Best Practices in

• Environmental Monitoring

• Program Development

• Investigations

3Company Confidential

FDA White Oak Campus

Division of Manufacturing and Product Quality

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research



Fictional Start-Up Facility – What FDA Investigators should expect to find


Inside Info

AGENDA• EM Program Development - Risk Based Approach to Qualification: Site Selection,

Sampling Plan Methods / Frequencies, and Data Handling

– Environmental Qualifications for RABS and Isolators

• EM Data: Understanding the Limits of EM Data w/Special Focus on Excursions and Investigations


CFR Part 211 CGMP for Finished Pharmaceuticals

211.42 Buildings and Facilities

• “The flow…shall be designed to prevent contamination.”• Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable;• (ii) Temperature and humidity controls;• (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure,

regardless of whether flow is laminar or nonlaminar;• (iv) A system for monitoring environmental conditions;• (v) A system for cleaning and disinfecting the room and equipment to produce aseptic

conditions;• 211.46• Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and

temperature…

Regulatory Expectations


Guidance and Standards: What should be expected of Cleanroom Manufacturers?

ISO 14644 / 2004 FDA CGMP

ISO 14644 Cleanrooms and Associated Controlled Environments –

• Part 1 (2015): Classification of Air Cleanliness by Particle Concentration

• Part 2 (2015): Monitoring to Provide Evidence of Cleanroom Performance Related to Air Cleanliness by Particle Concentration

• A risk assessment shall be undertaken in order to:

• - develop a monitoring plan by determining the factors that may affect the ability to maintain the agreed air cleanliness by particle concentration of the cleanroom or clean zone

• - determine the monitoring requirements to provide evidence of performance



Industry

No excuse for not knowing

• PDA

• PIC/S

• IEST

• ISPE

• PMF

• BPOG

• ASM

• …

Guidance and Standards: What should be expected of Cleanroom Manufacturers?

Regulatory

• EU Guidelines to CGMP for Medicinal Products Annex 1

• 2004 FDA CGMP Guidance for Industry Sterile Drug Products Produced by Aseptic Processing

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


Annex 1…revision

• 15 pages…to 50

• 127 clauses…to 269

• Mention of “risk” from 20 times…to 92

• References to “Risk Assessment” and “Risk Management” throughout


“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.”


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

“Monitoring locations should be based upon an assessment of risk.”

In case there was any doubt…


Historical Current (better!)

• Based on higher risk aseptic processes & opinion, ambiguous selection criteria

• Program tailored to specific facility and processes; criteria based on objective risk-based approaches

Risk based Approach to Site Selection, Sampling Plan Methods / Frequencies & Data


Risk Based Approach to: Site Selection, Sampling Plan Methods / Frequencies, & Data

•Cross-functional Group Project: Led by SMEs in Pharmacuetical Microbiology / Contamination Control

• Identify Risk Factors for Process & Area

• In-person Assessment of Risks: Process & Area

EM Program Development

•FMEA / Flow Charts / HACCP / Process Mapping



• Map the Area

• Grid overlay

• Specify Critical Functional Areas

• Suggest defining grid size by ISO classification (5, 7, 8) or Grade (ABCD)




Map the Area

Grid overlay

Specify Critical Functional Areas

Suggest defining grid size by ISO classification (5, 7, 8) or Grade (ABCD)


Examples:

• 0.5 m2 Grade A

• 4.0 m2 for B, C, D

or

• Grade A 1m2, Grade B 2m2, Grade C 3m2 and Grade D 4m2


Risk Criteria Rationalized Frequency

• Easy to Clean / Sanitize / Disinfect / Sterilize

• Proximity of Open Product or Product-Contact Parts

• Material Flow

• Personnel Presence & Movement

• Interventions: complex, simple, prolonged, routine, non-routine

• Nature & frequency of Interventions, Process Steps

• Based in principles of Risk, Science, & Logic

• 2 Factors most heavily weighed for Frequency

• Probability of Contamination

• Potential for Impact to Product Quality

• Differentiate by Grade

• Differentiate by Function

• High Traffic Areas – Material Pass-Through and Personnel Entryways

• Differentiate Floors, Walls, Ceilings, Equipment, Touch Points

Site Selection / Sampling Plan


General Attributes

• Follows a written & approved sampling plan– Traceability

• Performed by qualified / trained samplers

• Defined number of “rounds”

• At-Rest / In-Operation

• Acceptance Criteria– If initial EM qualification, may be informational or target levels

• Response, Resolution, Remediation

Implementation


EM Program – Can it demonstrate recovery after a loss of control, planned or unplanned?

Need to have a written plan

FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (Sept. 2004 Pharmaceutical CGMPs)

• “Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems or other utilities, and the impact of construction activities on facility control. Written procedures should address returning a facility to operating conditions following a shutdown.”

Question:


Environmental Qualifications for Isolators

Traditional EM design principles are inappropriate

Far lower or better rates of contamination thantraditional cleanroom

Additional equipment, sampling, etc. in a confined space with exceptional control

Spatial limitations

Non value-added monitoring increases cost & resource consumption

Advanced Aseptic Processing Technology


Test Results, Excursions, and Investigations

Principles to Avoid the Over-, Under-, and Mis-interpretation

of EM Data

Understanding the Limits of EM Data


Understanding the Limits of EM Data w/Special Focus on Excursions and Investigations

Cultivation-based Sampling

Accuracy at low levels (<25 CFU) is poor

Variability

EM Data Limits


The Great Plate Anomaly

Cultivation-Based Microbiology

~100 times more cells than colonies ≈ 99% “unculturable”

• Annu Rev Microbiol. 1985;39:321-46.

• Measurement of in situ activities of nonphotosynthetic microorganisms in aquatic and terrestrial habitats.

• Staley JT, Konopka A

https://www.ncbi.nlm.nih.gov/pubmed/3904603

https://www.ncbi.nlm.nih.gov/pubmed/?term=Staley%20JT%5bAuthor%5d&cauthor=true&cauthor_uid=3904603

https://www.ncbi.nlm.nih.gov/pubmed/?term=Konopka%20A%5bAuthor%5d&cauthor=true&cauthor_uid=3904603


LIMITS

0 – 60% Recovery

Dependent on Surface Type

Dependent on Operator Technique

Dependent on…

• Condition of microbe

• Temperature

• Humidity

• Media type

• Exposure time

• Incubation time

etc.

Understand Inherent Variability and Imprecision


Relevance of Sampling Method

Don’t overinterpret those 0 CFUs

25 cm2 contact plate in a 10’ x 10’ Room

1 floor plate = 0.03% of surface area


“Zero” Significance

Adapted from “Regulation of Aseptic Processing in the 21st Century”, 2011, Pharmaceutical Technology, Akers & Agalloco

Example of over-interpreting “0 CFU” results from EM

• 500 Air Changes per hour

• Cleanroom area of 500 m3

• Total volume of air = 250,000/m3 of air per hour

1,000 instruments each collecting 6 m3/hour could sample 6,000 m3 out of 250,000 m3…

…or just 0.24%


Where to Begin?

– Manned cleanrooms and work zones have microbial presence

– Systemic failures should have demonstrable causes

– Deviations from Standard Operating Procedure are risky

– Breach in primary control system(s) is a probable RC

– Involvement of Microbiology• Identification of contaminant(s)• Review of EM and relevant test histories

– Batch Record Review– Training records– Method validation

Investigations


Assess Validity of Sample Causes of Bad Investigations

• Sample collection

• Relevant Associated Testing? (warning, pitfall here)

• Sample Transport, Chain of Custody maintained?

• Appropriate Sample Storage Conditions?

• Analyst Qualification, Training, and Experience Level?

• Test Equipment Validated and Calibrated? Good Working Order?

• Assumption is still too pervasive that an aseptic processing environment is sterile, or at least must yield EM data that signifies sterility

• Ascribing qualities to microbial data that it does not possess over and under interpretation of EM data is common

• Seeing “patterns” or “trends” where no meaningful correlation exists

• Pressure to identify palatable RC



Evaluate Cleaning & Disinfection Program as a potential cause

• Disinfectant application conditions

• Time / Temperature

• Application method

• Personnel – experience, technique

• Water quality

• Extra shift

• New personnel

• Construction

• Chemical agent (conc., product quality)



Optimized Pitfalls

• Operator interviews

• First-hand observations

• Senior Management Support

• Empowered engaged employees

• Lack of true subject matter experts on staff

• Misapplication of technologies

• Misunderstanding of test methods

• Depth and breadth of staff experience

• Status Quo

EM Investigations


Holmes, Ockham & Logical Fallacies

Sherlock Holmes, “…when you have eliminated the impossible, whatever you’re left with, however improbable, is the truth.” The Sign of the Four, ch. 6 (1890), Sherlock Holmes in The Sign of the Four (Doubleday p. 111)

Investigations

William of Ockham, 14th century Franciscan friarNotable for problem-solving principle that states "entities should not be multiplied unnecessarily”Ockham’s Razor or "the law of briefness"


Logical Fallacies

AVOID THESE!

Investigations

Appeal to Probability

Post hoc ergo propter hoc

– After this, therefore because of this

Correlation Proves Causation

Cherry picking

Slippery slope

Appeal to Authority

Ad hoc hypothesis


Takeaways

Our biopharma company must have a qualified EM program for their facility

Developed and established using principles and tools of Risk Management

Cleanroom operators must understand microbiology and contamination control principles.

All personnel must receive initial and periodic training in aseptic processing, interventions, gowning, contamination control.

This training MUST be delivered by Subject Matter Expert(s), proficient in the topics they teach.

Data and Investigations of microbial contamination issues need to be looked at through different lens.

31

Thank You

Company Confidential

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