Risk Issues for Environmental Monitoring

8/3/2019 Risk Issues for Environmental Monitoring

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Q Pharma 2009

Risk Issues in the DesignRisk Issues in the Design

and Operation of Asepticand Operation of Aseptic

Processing FacilitiesProcessing Facilities

Nancy Tomoney

Associate Validation Manager

Q Pharma Inc.

Gowning Rooms and Procedures


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Why?Why?

Microbial contamination inside of aseptic processing rooms representsa grave product risk.

Supporting areas such as rooms dedicated to donning the sterile gownscan play a role in maintaining the inner core microbial free.

The construction of modern cleanrooms and HVAC systems provide asubstantially microbial free air when properly designed; but thoseprinciples are not fully and consistently applied to gowning rooms.

Primary sources are: people, equipment, materials and air.

It is people that continue to be the prime vectorand contributorofmicrobialcontamination.


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Room Design and HVACRoom Design and HVAC

Problem:

The construction of modern cleanrooms and HVAC systems provide

a substantially microbial free air when properly designed but

principles are not fully and consistently applied to gowning rooms. Reason for Problem:

Inadequate direction from the regulators

EMEA EU Annex 1 and ISO 14644

FDA USP and ISO 14644


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Identifying RisksIdentifying Risks


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EU Annex 1EU Annex 1

No mention of gowning areas


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US FDAUS FDA

Gowning is therefore a support area, a clean area that

needs to be controlled.


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USPUSP

Other support areas sample once to twice a week. Bad

suggested practice often applied to gowning areas.


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How to Get to BestHow to Get to Best

Good environmental control starts with design!

What are typical clean suite layouts?


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LayoutsLayouts

OK, But Not IdealOK, But Not Ideal


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LayoutsLayouts

BetterBetter


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LayoutsLayouts

BestBest


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Cleanroom Lifecycle AccordingCleanroom Lifecycle According

to ISO 14644to ISO 14644--44

Requirements

Planning and Design

Construction and Start-up

Testing and Approval

Documentation


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Cleanroom Lifecycle AccordingCleanroom Lifecycle According

to ISO 14644to ISO 14644--44

Annex A Control and segregation concepts

Annex B Classification examples

Annex C Approval of an installation

Annex D Layout of an installation

Annex E Construction and materials

Annex F Environmental control of cleanrooms

Annex G Control of air cleanliness

Annex H Additional specification of requirements to be agreed uponbetween purchaser/user and designer/supplier


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RequirementsRequirements

Is there a signed contract with defined User Specifications?

Is the construction required to meet ISO 14644 or EU

cleanrooms designation?

Are roles of contractors, designers, engineering staff and

specific SMEs defined in the Project Plan/VMP?

The assignment of tasks for the preparation, approval, execution,

supervision, documentation, statement of criteria, basis of design,

detailed design, construction, testing, commissioning andqualification.


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What are the operations to be carried out & any constraints

imposed by the operating requirements?

What are the required airborne particulate cleanliness class

or demands for cleanliness?

What are the critical environmental parameters including:

Specified set points,

Alert and action levels

Measurement methods to be used


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What is the contamination control concept, including

installation, operating and performance criteria, to be used

to achieve the required cleanliness level?

What are the methods of measurement, control, monitoringand documentation required to meet the parameters?

Is the entry or exit of equipment, apparatus, supplies and

personnel required to support the installation?


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What are the specified occupancy states selected from "as-

built", "at-rest" and "operational"?

Has the layout and configuration of the installation been

optimized for best control?

What are the critical dimensions and mass restrictions,

including those related to available space?


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What are the process and product requirements that affect

the installation?

What is the process equipment list with utility

requirements?

What are the maintenance requirements of the installation?


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Has the identification and evaluation of external

environmental influences been performed?

Are there any special considerations; additional information

required by the particular application?


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Planning and DesignPlanning and Design

Planning Procedure

Develop a project plan with all stakeholders.

Develop a process equipment list and include the critical

requirements for each piece of process equipment.Identify peak and average demand for each utility and

environmental control system.

Develop a contamination control concept shall be developed for

each zone of the installation.

Clean, with what, how often, air changes, etc.Review all specifications to financial and timescale requirements.


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Planning Procedure

The project plan shall include the following elements:

design documentation with support calculations;

cost evaluation; timescale evaluation and anticipated project complications;

design options with advantages and disadvantages and any

recommendations;

a review of maintenance requirements of the installation;

a review of the degree of flexibility to be included in the installation; a review of the stand-by capacities to be included in the installation;

a review of the constructability of the design of the installation;

a quality plan.

The completed project plan shall be reviewed and agreed upon

between all parties, including the contractor.


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Design

The design shall accommodate all of the relevant product and

process requirements in conjunction with the selected contamination

control concept.

The design shall conform to an agreed list of requirements, such as

building, environmental and safety regulations, good manufacturing

practice guidelines.

The design should be reviewed at periodic stages of development,

including final completion, to ensure compliance with the

specifications and the acceptance criteria.


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Good HVAC (Critical Areas)Good HVAC (Critical Areas)

Atypical

Class 100,

usually in

hoods and

for potent

compounds

Typical

Class 100,

for sterile

nonpotent

compounds

Class 10,000

or 100,000areas,

controlled but

not always

critical

Non drug


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Not the Best HVAC, but is it OK forNot the Best HVAC, but is it OK for

Gowning?Gowning?

Oral dose, LCO, and other non-sterile doses, medical

device assembly, and alas. gowning rooms.


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Air DisturbanceAir Disturbance


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Contamination ControlContamination Control


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Construction and StartConstruction and Start--upup

Construction of an installation shall comply with the

drawings and specifications.

Any changes required during the course of construction

shall be:checked for acceptance,

approved

and documented prior to implementation of the change in

accordance with a change control procedure.

Construction work, whether performed at a manufacturing

location or in situ, shall observe the specific contamination

control requirements of the quality plan.


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Gowning Room Air MovementGowning Room Air Movement

Typical Gowning Room Ideal Gowning Room


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Bad HVAC Design in Best RoomBad HVAC Design in Best Room

Critical AHU

Controlled AHU

Common AHU


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Better HVAC Design in Best RoomBetter HVAC Design in Best Room

Critical AHU

Controlled

subcritical

AHU

GMP AHU

Controlledsubcritical

AHU3

Controlled

subcriticalAHU3

Controlled

subcritical

AHU2

Controlled

subcritical

AHU2Critical AHU


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GowningGowning

Personnel Pre-

gowning

Personnel

Gowning


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Design RisksDesign Risks


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User RequirementsUser Requirements

User Requirements forGowning Area:

There will be a personnel entrance, pre-gowning and a separate

gowning room.

Personnel will enter through a pre-gowning room, ISO 8 / Class100,000.

They will enter gowning room from pre-gowning.

Personnel will gown in the gowning room.

Personnel will enter aseptic operations area from the gowning room.

Personnel will not be able to exit the aseptic area through thegowning room.

Access will be controlled (badging in and out is always a good idea)


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PrePre--GowningGowning

User Requirements for Pre-Gowning Area:

Entrance will be off the GMP corridor

Airflow can be mixed but is from ceiling to floor.

Temperature and humidity will be controlled.Total particulates will be ISO 8 (Class 100,000)

Pre-gowning has a sink, racks for hat coverings, foot coverings, and

pegs to hang lab coats (if required in GMP area)


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GowningGowning

User Requirements forGowning Area:

Airflow will be unidirectional or non-unidirectional.

Temperature and humidity will be controlled,

Viable and total particles will be controllable (total at least ISO 8 /Class 100,000.

Gowning room will have a sink, mirrors, racks for gowns, gloves,

booties, hoods.

They will enter controlled corridor from gowning room.


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A clean construction protocol for cleaning and cleaning proceduresshall be:

Developed as part of the quality plan and enforced to achieve the specifiedcontamination control requirements.

And includes security and access control The cleaning methods and methods to determine and approve the

achieved cleanliness shall be defined and documented in the qualityplan.

The cleaning of the air systems shall be specified and shall be carriedout:

at assembly,

before initial operation

and whenever rebuilding work,

repair work

and maintenance work are performed.


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In the case of start-up of new installations or re-starting

existing installations after repair or modification, final

cleaning of the cleanroom is necessary and provisions shall

be made for the removal of adherent, imported or releasedcontamination.

Before commencing any operational activities, the complete

and satisfactory function of the installation shall be

determined by tests defined in the project plan.


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During acceptance testing, commissioning and initial

operation, the personnel in charge of the installation shall

be trained.

Testing, approval of the installation and training shallinclude all relevant practices for proper cleanroom

operation, maintenance and in-process control.

The responsibility for providing training shall be defined.

When training is carried out, all relevant persons such asoperators, maintenance and service personnel should be

included.


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Testing and ApprovalTesting and Approval

General

During and upon completion of the construction of an installation, an

agreed series of documented tests shall be specified and

undertaken prior to operational use of the installation.

Construction approval

A systematic range of inspections, adjustments, measurements and

tests shall be carried out to ensure that each part of the installation

complies with the design requirements.


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Testing and ApprovalTesting and Approval

Functional Approval

A series of tests and measurements shall be carried out to

determine that all parts of the installation operate together to

achieve the required conditions in the "as-built" or "at-rest" states.

Operational Approval

A series of tests and measurements shall be carried out to

determine that the complete installation achieves the required

"operational" performance with the specified process or activity

functioning, and with the specified number of personnel presentworking in the agreed manner.


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DocumentationDocumentation

General

Details of a completed installation (including instrumentation

calibration) and all operation and maintenance procedures shall be

documented. Documents shall be made readily available to all

personnel responsible for startup, operation and maintenance of the

installation.

Such personnel should fully understand the documentation.


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Record of an Installation

Details of the completed installation shall be provided and shall

contain:

a description of the installation and its function;

a set of final and approved performance test data, derived from the

tests carried out in accordance with clause 7 of this part of ISO 14644,

recording the values of all conditions defined in the specification for the

installation and achieved during the commissioning, testing and start-up

procedures;

a set of drawings, diagrams (e.g. layout of wiring, piping andinstrumentation) and specifications describing the completed and

approved "as-built" installation and its components;

a list of parts and equipment and any recommendation for stocking

spare parts.


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Operational Instructions

Each installation or system shall be provided with a clear set of

operating instructions. Such operating instructions shall contain:

schedules of checks and inspections to be completed prior to the start-

up of an installation;

schedules of the acceptance range of the critical performance

parameters specified;

procedures to start and stop the installation under normal and failure

mode situations;

procedures to be adopted in the event of alert or action levels beingreached.


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Instructions for Performance Monitoring

Performance-monitoring of an installation is essential to

demonstrate satisfactory operation.

Documentation shall include: test and measurement frequency;

description of test and measurement methods, (or reference to

standards and guidelines);

action plan in the event of non-compliance;

frequency required for assembly, analysis and retention of performancedata to enable trends to be analyzed.


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Maintenance Instructions

Maintenance shall be implemented in accordance with a specified

maintenance plan.


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Maintenance Instructions

Maintenance and repairs shall be carried out during theconstruction, commissioning, testing, start-up and normal operationof an installation. The following items shall be defined:

Safety procedures prior to carrying out maintenance or repairs; Maintenance actions to be taken when the acceptance range of any

critical performance parameter is exceeded;

Agreed permitted adjustments;

Methods of making permitted adjustments;

Methods of checking and calibrating control, safety and monitoringdevices;

requirements for checking and replacing all wearing parts

Procedures for cleaning of the installation or components prior to,during and after maintenance work;

Actions, procedures and tests required after maintenance is completed;

Any user-specific or relevant regulatory authority requirements.


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Maintenance Record

A documented record of any maintenance carried out upon the

installation during construction, commissioning and start-up shall be

maintained.

The following items shall form part of the record:

Defined maintenance tasks;

Identification and approval of personnel undertaking the maintenance;

Date of carrying out the maintenance;

Conditions prior to undertaking the maintenance;A list of spare parts used;

A report upon completion of the maintenance.


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Record of Operation and Maintenance Training

A documented record of training shall be maintained.

The following items shall form part of the record:

Definition of the training content; Identification of personnel providing and receiving the training;

Training date and duration;

A report upon each period of training as it is completed.


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Gowns, the Second SkinGowns, the Second Skin

Specially designed uniforms (gowns) and gowning

procedures are fundamental barriers or filters to protect

the environment.

Issues with gowns failingProper gowning procedures

How cleanroom and HVAC technology can be applied to gowning

rooms

Ideal layout design for an entering and exiting a controlled

environment


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PrePre--GowningGowning

Remove outer coat

Wash hands

Don bonnet and foot covers


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Gowning and BioburdenGowning and Bioburden

Poorly designed gowning procedures and uniforms plus

inadequate air handling systems in gowning rooms prove to

be a conduit for introduction of microorganisms including

mold and skin microorganisms.


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Gowning PracticesGowning Practices

Top to bottom for gowning

Top to bottom for degowning

No makeup, jewelry, electronic devices, etc.

Initial qualification and some form off continued follow-up

with period of full to partial evaluation.

Gowning practice is to protect the product from the

personnel.G

owning should be based on the type of theproduct & its claim for sterility or microbial control (Non-

sterile)


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Gowning & Gowning TrainingGowning & Gowning Training --

General Good PracticesGeneral Good Practices

A detailed description of microbiological training programs is included in

PDA Technical Report No. 35: Competency Based Training Programs.

Training/Certification of personnel for environmental monitoring may

include but is not limited to, the following:

Personal hygiene/habits Cleanliness of hair, skin, teeth, fingernails and clothing

No make-up, nail polish, perfume or cologne, sculptured fingernails, gum, candy

No eating, drinking, chewing or smoking in the cleanrooms

Illness

Report all colds, flu, infections, wounds or sunburn

Report all disease or chronic skin conditions, open sores

Clothing

Dedicated plant or area uniforms, and shoes required

No watches, rings, exposed jewelry such as body piercing, protruding jewelry

Protective dedicated clothing required


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Training/Certification contd:

Introduction to microbiology

General microbiology

Common sources of microorganism types

How do they grow What are the sources of nutrition

Environmental conditions for growth

Methods of control

Sanitization Procedures

Admittance of items

Disinfectants versus Sanitization Sterile versus sanitized

Patient safety to non-sterile product

Methods of microorganism control

Application of Disinfectants

Introduction to aseptic techniques


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Training/Certification contd:

Microbiological gowning certification

Documented training in a classroom on proper gowning technique by certified

trainers

Personnel are documented to properly gown (i.e., not add contamination) via

gowning certification Perform proper gowning three times as and initial

certification and a minimum of one certification on an annual basis if the

personnel routinely is monitored during normal manufacturing.

Gowning certification will include additional sampling sites beyond those

routinely monitored - the forehead, mask, neck area, back of head, chest area,

garment zipper, arms, fingers.

Routine monitoring may include garment samples from both forearms,shoulders, zipper area of garment, and finger impressions from both hands.

Overall profiles may also be evaluated.

Participation in media fills to demonstrate aseptic skill level.

All training and certification activities should be documented and kept as part of

the employee file.


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Ongoing and Retraining

Gowning Certification

If samples from garment or finger impressions (dabs) exceed the

alert/action level, the employee should be retrained on all appropriate

procedures and re-certified before entry into the aseptic area isapproved. It is good practice to re- qualify every six months.

Routine Monitoring

If samples from garment or finger impressions exceed the alert/action

level, it may require that the employee should be retrained on

appropriate procedures and re-sampled at the earliest possible time. If

a trend of over alert/action level occurrences excursions develops,

further corrective action, which may include complete re-certification or

reassignment to new duties, may be considered. If this course of action

is not effective, the employee may need to be reassigned to other job

duties outside the aseptic area.


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Ongoing and Retraining

Annual retraining and re-certification should occur for:

all employees required to work in an aseptic environment.

all employees involved in aseptic manufacturing should participate in a

process simulation test (media fill) at least annually.

After a long absence,

e.g., sabbaticals, medical leave, family leave, and so forth, (say 30 days)

an individual requires to undergo re-training and re-qualification to ensure

effective conformance to the systems.

All retraining and re-certification activities should be documentedand kept as part of the employee file.


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GowningGowning

First pair gloves

Boots

Bunny suit, etc

Second pair gloves

Goggles


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Non Sterile GowningNon Sterile Gowning


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Non Sterile GowningNon Sterile Gowning


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Sterile GowningSterile Gowning


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Training and FollowTraining and Follow--upup

Control of microbial contaminants from personnel is

addressed by providing intense and dedicated training and

supervision on aseptic processing methodologies.


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ReferencesReferences

FDA

US Food and Drug Administration Guidance for Industry Sterile

Drug Products Produced by Aseptic Processing Current Good

Manufacturing Practice, September 2004.

EMEA

EU Annex 1 European Union Volume 4

The Rules Governing Medicinal Products in the European Union

Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal

Products for Human and Veterinary Use Annex 1 Manufacture of Sterile

Medicinal Products, 14 February 2008


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ISO

ISO 14644-1, Cleanrooms and associated controlled environments

Part 1: Classification of air cleanliness, 05/01/1999


Part 2: Specifications for testing and monitoring to prove continuedcompliance with ISO 14644-1, 09/15/2000


Part 3: Test Methods, 12/15/2005


Part 4: Design, construction and start-up, 4/01/2001


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ISO


Part 5: Operations, 12/06/2001


Part 6: Vocabulary, 2007


Part 7: Separative enclosures (clean airhoods, gloveboxes,

isolators, mini-environments), 07/22/2001


Part 8: Classification of air cleanliness, 08/15/2006


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ISO


Biocontamination Control- Part 1: General principles and methods,

09/01/2003

ISO 14698-2, Cleanrooms and associated controlled environments Biocontamination Control- Part 2: Evaluation and interpretation of

biocontamination data, 11/01/2004


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PDA

PDA Technical Report No. 13 Revision 2 Fundamentals of an

Environmental Monitoring Program, September/October 2001

Coming Soon: PDA Technical Report No. 13 Revision 2

Fundamentals of an Environmental Monitoring Program

Environmental Monitoring: A Comprehensive Handbook, Volume I ,

Jeanne Moldenhauer, July 2005

Environmental Monitoring: A Comprehensive Handbook, Volume II ,

Jeanne Moldenhauer, July 2005

Environmental Monitoring: A Comprehensive Handbook, Volume III, Jeanne Moldenhauer, 2009

Environmental Monitoring: A Comprehensive Handbook, Protocol

CD , Jeanne Moldenhauer, July 2005


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Contact InformationContact Information

Nancy Tomoney

Associate Validation Manager

Q Pharma Inc.

22 South StreetMorristown NJ 07960

(973)656-0248 ext. 2007

[email protected]