risk issues environmental monitoring of cleanrooms

© Q Pharma 2009

Risk Issues in the Design Risk Issues in the Design and Operation of Aseptic and Operation of Aseptic

Processing FacilitiesProcessing Facilities

Nancy TomoneyAssociate Validation Manager

Q Pharma Inc.

Gowning Rooms and Procedures

Why?Why?

Microbial contamination inside of aseptic processing rooms represents a grave product risk.

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

The construction of modern cleanrooms and HVAC systems provide a substantially microbial free air when properly designed; but those principles 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 vector and contributor of microbial

contamination.

Good Design, Low Bioburden, Bad Good Design, Low Bioburden, Bad Design, High BioburdenDesign, High Bioburden

Control of microbial contaminants from personnel is addressed by providing intense and dedicated training and supervision on aseptic processing methodologies.

Specially designed uniforms (gowns) and gowning procedures are fundamental barriers or “filters” to protect the environment. How cleanroom and HVAC technology can be applied to gowning

rooms Ideal layout design for an entering and exiting a controlled

environment Proper gowning procedures Issues with gowns failing

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

Identifying RisksIdentifying Risks

EU Annex 1EU Annex 1

No mention of gowning areas

US FDAUS FDA

Gowning is therefore a support area, a clean area that needs to be controlled.

USPUSP

Other support areas sample once to twice a week. Bad suggested practice often applied to gowning areas.

How to Get to BestHow to Get to Best

Good environmental control starts with design! What are typical clean suite layouts?

LayoutsLayoutsOK, But Not IdealOK, But Not Ideal

Layouts Layouts BetterBetter

Layouts Layouts BestBest

Common GMP Corridor

Eqiupment / Mateials In1st Cleaning

Pre-gown, Personnel In

Gowning

2nd and subsequent

cleaning

Cleanroom Lifecycle According Cleanroom Lifecycle According to ISO 14644-4to ISO 14644-4

Requirements

Planning and Design

Construction and Start-up

Testing and Approval

Documentation

Cleanroom Lifecycle According Cleanroom Lifecycle According to ISO 14644-4to ISO 14644-4

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 upon between purchaser/user and designer/supplier

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 and qualification.


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


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, monitoring and documentation required to meet the parameters?

Is the entry or exit of equipment, apparatus, supplies and personnel required to support the installation?


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?


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?


Has the identification and evaluation of external environmental influences been performed?

Are there any special considerations; additional information required by the particular application?

Planning and Design Planning 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.


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.


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.

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 100,000 areas, controlled but not always critical

Non drug

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

Air DisturbanceAir Disturbance

Contamination ControlContamination Control

Construction and Start-upConstruction and Start-up

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.

Gowning Room Air MovementGowning Room Air Movement

Typical Gowning Room Ideal Gowning Room

Bad HVAC Design in Best RoomBad HVAC Design in Best Room

Critical AHU

Controlled AHU

Common AHU

Better HVAC Design in Best RoomBetter HVAC Design in Best Room

Critical AHU

Controlledsubcritical

AHU

GMP AHU


AHU3


AHU3


AHU2


AHU2Critical AHU

GowningGowning

Personnel Pre-gowning

PersonnelGowning

Design RisksDesign Risks

User RequirementsUser Requirements

User Requirements for Gowning Area: There will be a personnel entrance, pre-gowning and a separate

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

100,000. 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 the

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

Pre-GowningPre-Gowning

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)

GowningGowning

User Requirements for Gowning 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.


A clean construction protocol for cleaning and cleaning procedures shall be: Developed as part of the quality plan and enforced to achieve the specified

contamination 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 quality plan.

The cleaning of the air systems shall be specified and shall be carried out: at assembly, before initial operation and whenever rebuilding work, repair work and maintenance work are performed.


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 released contamination.

Before commencing any operational activities, the complete and satisfactory function of the installation shall be determined by tests defined in the project plan.


During acceptance testing, commissioning and initial operation, the personnel in charge of the installation shall be trained.

Testing, approval of the installation and training shall include 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 as operators, maintenance and service personnel should be included.

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.

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 present working in the agreed manner.

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.


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 and instrumentation) 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.


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 being

reached.


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 performance

data to enable trends to be analyzed.


Maintenance Instructions Maintenance shall be implemented in accordance with a specified

maintenance plan.


Maintenance Instructions Maintenance and repairs shall be carried out during the

construction, commissioning, testing, start-up and normal operation of 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 monitoring

devices; 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.


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.


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.

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 failing Proper gowning procedures How cleanroom and HVAC technology can be applied to gowning

rooms Ideal layout design for an entering and exiting a controlled

environment

Pre-GowningPre-Gowning

Remove outer coat

Wash hands

Don bonnet and foot covers

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.

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. Gowning should be based on the type of the product & its claim for sterility or microbial control (Non-sterile)

Gowning & Gowning Training - Gowning & 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


Training/Certification cont’d: 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


Training/Certification cont’d: 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.


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 is approved. 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.


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 documented and kept as part of the employee file.

GowningGowning

First pair gloves

Boots

Bunny suit, etc

Second pair gloves

Goggles

Non Sterile GowningNon Sterile Gowning

Sterile GowningSterile Gowning

Training and Follow-upTraining and Follow-up

Control of microbial contaminants from personnel is addressed by providing intense and dedicated training and supervision on aseptic processing methodologies.

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


ISO ISO 14644-1, Cleanrooms and associated controlled environments

Part 1: Classification of air cleanliness, 05/01/1999 ISO 14644-2, Cleanrooms and associated controlled environments

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

ISO 14644-3, Cleanrooms and associated controlled environments Part 3: Test Methods, 12/15/2005

ISO 14644-4, Cleanrooms and associated controlled environments — Part 4: Design, construction and start-up, 4/01/2001



Part 5: Operations, 12/06/2001 ISO 14644-6, Cleanrooms and associated controlled environments

Part 6: Vocabulary, 2007 ISO 14644-7, Cleanrooms and associated controlled environments

Part 7: Separative enclosures (clean air hoods, gloveboxes, isolators, mini-environments), 07/22/2001

ISO 14644-8, Cleanrooms and associated controlled environments Part 8: Classification of air cleanliness, 08/15/2006



– 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


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

Contact InformationContact Information

Nancy Tomoney

Associate Validation Manager

Q Pharma Inc.

22 South Street

Morristown NJ 07960

(973)656-0248 ext. 2007

[email protected]

mailto:[email protected]