IVT’s Contamination Control Week June 25-27, 2012

Boston, Massachusetts

Session 5 • Understand the Evolving Regulations for Aseptic Cleaning and

Environmental Monitoring

For more information on aseptic cleaning and environmental monitoring, please visit www.ivtnetwork.com.

Use the promo code SLIDE1 for a 10% discount on a membership!

CONTACT INFORMATION for Course Leader:

David Vincent, CEO Validation Technologies, Inc. San Diego, CA Office: 800-930-9222 Fax: 858-638-5532 Email: davidv@validation.org

Topics Addressed

§  Regulatory requirements & expectations §  Potential sources and types of microbial

contamination §  Implementation of microbial control

measures §  Disinfection/Sanitization §  Environmental monitoring

Microbiological control is a regulatory requirement

Part 1:

CFR 21- 211.113 (a)

Control of Microbiological Contamination Microbial “Appropriate written procedures, designed to prevent objectionable organisms in drug products not required to be sterile, shall be established.”

§  Control of bioburden §  Absence of objectionable organisms

WHAT IS CONTAMINATION?

§  There are two types of contamination. Non-viable (Particulate)

–  Air Filtration – Materials shedding

Viable (Microbiological or Bioburden) – Molds –  Bacteria –  Viruses

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Viable Contaminants §  Viruses §  TSEs (transmissible Spongiform encephalopathies §  Fungi §  Bacterial §  Pyrogens (Endotoxin) §  Mycoplasma §  Biological Based Components (DNA, foreign proteins,

etc.)

NONVIABLE CONTAMINATION

§  This is any type of contamination that is not viable. It is usually filterable. For example: §  Dirt, sand, powders, etc. §  Particulate §  Debris §  Molding flash §  Chemical contamination such as crystals, etc. §  Oils and Mold Release agents §  Insect parts

§  Controlled room classifications are defined by particulate contamination sizes and numbers.

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What is Contamination Control?

§  Contamination control is not simply a task or function. It is a science and applied technology that interacts continuously with all products, processes, materials, equipment, and personnel entering the manufacturing areas.

Microbiological Control §  Identify possible sources of

contamination §  Identify possible types of contamination

likely to occur §  Implement and validate/qualify

preventative and control measures

Possible Sources of Contamination

§ Raw Materials/Excipients § Equipment and Process § Environment/Facility § Personnel

Raw Materials/Excipients

§  Bioburden in raw materials and excipients v  natural vs synthetic products v  water activity level

§  Bioburden in water systems v  potable water, purified water, WFI v  biofilm

Equipment and Process

§  Process and Equipment Design

§  Material/Surface §  Unprotected storage tanks §  Back flow §  Perforated heat exchangers

§  Carbon filters/DI resins/membrane filters

§  Sampling/transfer hoses

§  Valves §  Dead legs

Facility § Facility design § Air handling system § Construction materials § Finish materials

Personnel §  Major potential source of microbial

contamination v  Exposed skin (flakes, oils) v  Hair v  Clothing fibers v  Dirt v  Cosmetics v  Tobacco smoke v  Behavior

Regulatory Expectations Related to Cleanroom Operations

Part 2:

Facilities: Cleanroom Classification

FS209 Cleanroom

classification

ISO 14644-1 Cleanroom

classification≥0.5um

particles/m3

Viable Microbes(cfu/m3)

Ave Airflow Velocity

(fpm)Air

changes/hr

100,000 8 3,520,000 100 5-10 5-48

10,000 7 352,000 10 10-15 60-90

1000 6 35,200 7 25-40 150-240

100 5 3,520 1 40-80 240-480

§  a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.

§  b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A.

§  c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis.

§  d- The additional use of settling plates is optional. §  e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

Equipment and Process

§  CFR 211.63, “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”

§  Q7A, 5.15, “Closed or contained equipment should be

used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.”

Equipment and Process

§  Equipment v  easily disassembled and cleaned v  use sanitary fittings and valves/avoid dead legs v  product contact surfaces resistant to corrosion v  store cleaned equipment in a sanitary condition

Equipment and Process §  Equipment flow and location

v  no cross flow of clean and dirty and contaminated equipment/materials

§  Process

v  evaluate each step in a process for the potential of microbial contamination

v  use closed systems whenever possible v  open operations should be contained within HEPA

stations

Environment & Facility

§  Flooring and wall materials must be easily cleaned

§  Surfaces must be resistant to chemicals, abrasion, and flaking

§  Ensure concave coving at the junction of walls and floors

§  Floors must be sloped toward the drain §  Clean/sanitize floors daily §  Cover floor drains when not in use §  Avoid standing water

Environment & Facility §  Evaluate traffic patterns and room capacity §  Production and packaging areas need to be

under positive pressure §  Establish and monitor operating parameters and

environmental controls §  Use HEPA filtration systems §  Clean up spills immediately §  Cover air ducts, pipes, and light fixtures §  Avoid build-up of dust and moisture

accumulation

Cleaning and Disinfection

Part 3:

Disinfection/Sanitization Program

•  Cleaning/Sanitization is a regulatory requirement

•  Cleaning should not be confused with disinfection

•  A cleaning program is not complete without contamination control

Disinfection/Sanitization Program

§  CFR211.56 (b) “ There shall be written procedures assigning

responsibilities for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.”

Preparation and Use of Disinfectants

Preparation and Storage •  EC Guide, Annex 1,

“Disinfectants and detergents should be monitored for microbial contamination: dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in grade A and B areas should be sterile prior to use.”

Current regulatory expectations for use of disinfectants Rotation

•  EC Guide, Annex 1, 37 “Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains.”

•  ISO Recommendation •  Industry Practice

Product Classification

§  Sanitizers v  proper use results in 99.9% (3 log) reduction of bacteria v  cannot handle soil; use on pre-cleaned surfaces

§  Disinfectants v  proper use results in 100% (> 4 log) reduction of bacteria and

yeast. Limited reduction for mold. v  most have surfactants/cleaning ability

§  Sterilants v  proper use results in 100% (> 6-7 log) reduction of all

microorganisms, including bacterial spores. v  require application on pre-cleaned surfaces

Disinfection efficacy

§  Suitability, efficacy & limitations of disinfectant agents and procedures should be assessed.

§  The disinfection program should include the use of a sporicidal agent used according to a written schedule and when environmental data suggests presence of spore forming agents (Baccilus spp.).

Endospores Mycobacteria

Fungal Spores Small Non-enveloped viruses (polio, rotavirus, rabies)

Vegetative Fungal Cells Enveloped Viruses (Herpes, Hepatitis B, Hepatitis C, HIV)

Vegetative Bacteria

Most Resistant

Least Resistant

Disinfectant Efficiency

Equipment and bacteria

Even seemingly smooth surfaces can harbor bacteria !

Scanning electron micrograph of Listeria monocytogenes forming a biofilm in soy on a stainless steel chip. Courtesy of Professor Amy Wong.

Cleaning/Sanitization Program An effective cleaning and sanitization

process is attained by: §  Treatment with strong acids and bases §  Use of high velocity hot water or steam §  Use of detergents and/or sanitizers §  Rinsing with high quality water (Purified or WFI) §  Use of solvent rinses §  Drying at elevated temperatures

Disinfectant Selection

§  Population and types of organisms §  Spectrum of activity of disinfectant §  EPA registrations §  Method of application §  Contact time §  Nature and surface to be disinfected §  Compatibility of surface with disinfectant

Disinfectant Selection

§  Corrosiveness of disinfectant §  Organic compounds present on surface §  Operator safety §  Compatibility with cleaning agents §  Planned rotation of disinfectants §  Needed steps to avoid contamination of

pharmaceutical products by disinfectant §  Need for residual bactericidal activity

Disinfectant Selection - Other Factors to Consider

§  Quality, sterility, and stability of product §  Ease of application §  Cleaning ability §  Supporting vendor documentation §  Cost and availability §  Factors that may affect performance (temp.,

organic matter, contact time, pH, etc…) §  Regulatory expectations/regulations

Current regulatory expectations for use of disinfectants §  Disinfectants Qualification

v  Studies to evaluate the effectiveness of the disinfectants as they are used and prepared

v  Studies to evaluate the storage conditions of disinfectants for possible loss of efficacy

v  Use of environmental isolates in the qualification studies

v  Neutralization studies

Disinfectant Qualification - Studies

In-Situ §  Use actually cleaning procedures §  Monitoring pre and post cleaning at worst-case conditions/

document activities §  Increased number of sample sites §  Compare EM data before & after

In-Vitro §  Surface Tests (use of coupons or pieces of equipment/

material) §  Carrier Tests (AOAC method) §  Use-Dilution Tests (modified AET )

Disinfectant Qualification - Studies

Typical Test Organisms §  Escherichia coli - ATCC 8739 §  Pseudomonas aeruginosa - ATCC 9027 §  Staphylococcus aureus - ATCC 6538 §  Bacillus subtilis - ATCC 6633 §  Candida albicans - ATCC 10231 §  Aspergillus niger - ATCC 16404 §  Environmental isolates

Disinfectant Qualification Surface Test

§  Preferred method by inspectors §  No guidance document available §  Must select types of surfaces (coupons) §  Variable microbial challenge level §  Quantitative method §  Must select contact times (1-5-10 minutes) §  Variable test conditions (wet vs dry) §  Sampling/recovery technique (swab, rinse, contact

plate) §  Need neutralization studies

Disinfectant Qualification - User’s Approach/Decisions

§  Type of agent and materials/surfaces and sites to be evaluated.

§  Testing protocol (In-vitro vs In-situ) §  Types of challenge organisms §  Contact times §  Sampling methods (swab, rinse, or contact

plate)

Disinfectant Qualification - Acceptance Criteria

§  Surface Tests v  ≥ 3-log reduction vegetative bacteria and fungi v  ≥ 2-log reduction spore-forming bacteria

§  Use-Dilution Tests v  ≥ 4-log reduction (disinfectant properties) v  ≥ 6-log reduction (sporicidal properties)

§  Carrier Test v  AOAC criteria

§  In-situ Test v  counts not to exceed alert levels

Environmental Monitoring Program

Part 4:

Monitoring and Trending

§  Establish an EM program §  Employee training and monitoring §  Enforce personal hygiene §  Enforce cGMPs §  Schedule regular PMs §  Product bioburden testing/trending §  Re-qualification vs on-going verification of

cleaning (bioburden and endotoxin) §  Change control

EM Program §  Regulatory requirement §  Must be tailored to a facility §  Must be manageable and efficient §  Must be well documented §  Must be defendable §  Must not add possible sources of contamination

into the environment §  Do not rely solely on EM data for assurance of

product quality

EM Program

EM is a tool to assist a company manage the microbiological control program

EM Program

Choice of Equipment §  Active vs passive §  Air and surface monitoring devices §  Detection of potential problems must be

done in a timely manner §  Sampling activities should not contribute to

contamination of the process

EM Program

Test Methods §  EM procedures must be qualified §  Use same methods used during qualification studies §  Viable and non-viable monitoring §  Use of specific media for fungi: is it really needed? §  Monitoring for anaerobes: is it really needed? §  Levels are established based on industry guidelines

and/or historical data

EM Program

Frequency and Sites §  Depends on area being monitored §  More intensive monitoring for “cleaner”

areas §  Usually frequency is reduced once

qualification is complete §  Trend towards continuous monitoring §  Site selection: depends on room design,

activities, equipment and personnel flow

EM Program

Data Management §  Results are retrospective §  Useful information can be obtained by trending

data §  Evaluate data based on Alert and Action Levels §  Identify isolates §  Frequent isolates should be maintained and used

in challenge studies

EM Program - Hot Topics

§  EM data linked to batch release EC Annex 1, 5 “Where aseptic operations are performed, monitoring should be frequent…Results from monitoring should be considered when reviewing batch documentation for finish product release…”

§  EM requirements for non-sterile operations

§  Use of PAT and Rapid Methods

EM Program – Focus of Regulatory Inspections

§  Create presentation describing program v  area classifications v  methods v  frequency v  rationale for choice of sites v  rationale for setting alert and action levels v  describe data management and trending

§  Create trend reports for each area v  tabular and graphical format v  trend by values and organisms

§  Create executive summary reports v  address deviations, adverse trends, CAPA

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Thank You!!