regulatory considerations for environmental monitoring

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Regulatory Considerations for Environmental

Monitoring

FDA Compliance for Sterile and Non-sterile Products

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Defining Environmental Requirements for Sterile and Nonsterile Production

The regulators require environmental monitoring for sterile production, but why do I need an environmental monitoring program for nonsterile production? EM is a basic requirement across multiple regulated industries;

food, cosmetics, nutriceuticals, drugs and devices. It is a measure of cleanliness of a utility, and therefore the biological

safety of the product being manufactured; manufacturing is after all a people process and people are the primary contributors of microorganisms in any manufacturing industry.

Extent of maintaining environmental control to prevent contamination depends on the type of product, the route of administration and the health of the person consuming that product.

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People are part of the process!!!!!


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What FDA states on contamination control and its impact on non sterile products: In both Pharmaceuticals and Medical Devices the FDA evaluates

the process against the: The laws in the Code of Federal Regulations applicable to the product

and the manufacturer The pharmaceutical NDA/ANDA or device application claim of product

sterile packaging or non sterile packaging Potential for the product to promote or harbor pathogenic

microorganisms• Impact on the patient

• Impact on the product

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The CFR, USP/NF, EU Volume 4 Annex 1, ISO 14644 & 14698 and how they relate to environmental monitoring requirements. The nature of your environmental monitoring program

will depend on a number of issues: Industry: pharmaceutical, medical device, nutriceutical Product claim: sterile, non-sterile, microbiologically controlled Regulatory body governing point of sale to consumer Route of delivery of the product

The CFR, USP/NF, EU Vol. 4, Annex 1, ISO 14644 & 14698 all contain valuable information on establishing, controlling your EM Program in relation to the product.

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The Core Requirements, HVAC, Cleaning and Facility Design

What Are the Core Requirements? Products Sold as Sterile

HVAC requirements, room construction & particulate monitoring as defined by the ISO 14644 documents

Micro requirements defined by FDA or EMEA depending on point of sale of sterile product

• Both Non-viable and Viable particles must be controlled

Products Sold as Non-Sterile HVAC requirements and room design defined by engineering design

for the room/facility Typically no particulate requirements, but maybe product specification

requirement Micro requirements defined by company policy and product micro

susceptibility

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The role of effective cleaning in controlling microorganisms Cleaning agents must be antimicrobial (USA need EPA

registration claims, EU has EU registration claims) Cleaning agents must be effective against the organisms

in the environment used Whether a sterile product or non sterile product, you

want to follow clean room cleaning regimes Need dedicated qualified clean room cleaners

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How to pick good cleaning and disinfection agents Need at least two and at least one of the cleaning agents

should be sporicidal Compatible with clean room surfaces and with other

cleaning agents; not leave a sensory residual Effective against microorganisms in the room Nontoxic to personnel Readily obtainable Comes with good technical support

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HVAC basics for effective contamination control Adequate pressure differentials Sufficient air changes, air changes for aseptic are

governed by ISO 14644 ISO 14644 is a general clean room standard that is applied in

aseptic processes.

HVAC System needs to be properly maintained and serviced

Defined temperature and or humidity (if required); ranges with alerts and alarms

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Facility design and construction, good ideas to implement and bad practices to avoid Need to provide architect/engineering planner with critical user

requirements for the facility based on the product being manufactured (sterile or non-sterile)

Why would you want to build a aseptic facility for a non-sterile product?

In the USA, it is a good idea to consult with the local FDA office, they are eager to assist you. Help now can prevent trouble later

Payment to contractors should be incomplete until the facility meets the environmental requirements in the design documents

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Precursor Activities

Validation, what you need to know and do Requirements are defined by whether you make a sterile

product or a non-sterile product Should do good engineering studies prior to starting

validation, allows you to tweak the facility before starting validation.

Validation activities Defined by validation master plan, VMP Cleaning agent qualification HVAC Controls Cleaning to remove soils from the room/facility

• Semi-annual, routine, and following actions and alerts according to approved SOPs

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Writing SOPs SOPs need to complete, detailed and approved prior to

validation SOPs that are method related, such as cleaning, should

be effectively demonstrated prior to approval and validation

SOPs need multiple approvals, facilities, manufacturing, microbiology as well as any other stake holders

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Writing good PQs The PQ is a demonstration of the room to meets its user

requirements PQs should be done under static and dynamic

conditions. Effective demonstrations of room requirements under static conditions must be demonstrated before dynamic conditions.

PQs are used to establish routine testing (monitoring, HVAC maintenance, cleaning) and to establish action and alert limits

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Method Selection and Data Collection

Selecting sample methods, don’t make it harder then it has to be Sample for the type of product (sterile/non-sterile) in the

room Select appropriate equipment recognized by industry to

perform sampling When bringing up a new facility, it’s is best not to be the guinea

pig for new technology

Establish any incubation requirements prior to PQs There are difference between continuous particle

monitoring systems, and point of testing particulate sampling

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Site Selection and Data Collection

The logic of picking air and surface sites to prove effective cleaning Need to visit the room/facility to select sample sites Select areas to test where people and equipment come

in contact Select critical sites that can alter product integrity if

compromised Select areas that could have dead air

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Common Mistakes

A cross section of FDA citations, 483 and Warning Letters from poor EM programs: 483s Warning Letters

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Common Mistakes

Excerpts from warning letters.doc

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Common Mistakes

For Pharmaceutical Companies Citation i.e: CGMP for Finished Pharmaceutical /

Adulterated

For Medical Device Companies: Citation i.e: CGMP/QSR/Medical Devices/Adulterated

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Referenced Material

The CFR United States Code of Federal Regulations.

Specifically Title 21.

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Referenced Material

FDA US Food and Drug Administration Compliance Policy Manual #

7382.845, Inspection of Medical Device Manufacturers, June 15, 2006

US Food and Drug Administration FDA 97-4179, Medical Device Quality Systems Manual: A Small Entity Compliance Guide, First Edition (Supersedes the Medical Device Good Manufacturing Practices Manual), December 1996

US Food and Drug Administration, Guide to the Inspections of Pharmaceutical Quality Control Laboratories, July 1993

US Food and Drug Administration, Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories, July 1993

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Referenced Material

FDA ICH Q2A International Conference on Harmonisation of

Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline Text on Validation of Analytical Procedures, October 27, 1994 (ICH Q2A)

ICH Q2A International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline Text on Validation of Analytical Procedures: Methodology, November 6, 1996 (ICH Q2B)

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Referenced Material

USP/NF United States Pharmacopeia/National Formulary,

Chapter <1116>, Microbiological Evaluation of Cleanrooms and Other Controlled Environments

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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Referenced Material

ISO International Organization for SStandardization. Several

documents: ISO 13465:2003, Medical devices — Quality management

systems - Requirements for regulatory purposes 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

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Referenced Material


documents: ISO 14644-5, Cleanrooms and associated controlled

environments 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

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Referenced Material


documents: ISO 14698-1, Cleanrooms and associated controlled

environments – 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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Citations

The Code of Federal Regulations: §21 CFR211.67 (a) Equipment cleaning and

maintenance (a) Equipment and utensils shall be cleaned, maintained, and,

as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

§ 211.84 (c) (1) Testing and approval or rejection of components, drug product containers, and closures

(c) (1) The containers of components selected shall be cleaned when necessary in a manner to prevent introduction of contaminants into the component.

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Citations

The Code of Federal Regulations: § 211.84 (d) (6) Testing and approval or rejection of

components, drug product containers, and closures (d) (6) Each lot of a component, drug product container, or

closure with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.

§ 211.113 (b) Control of microbiological contamination (b) Appropriate written procedures, designed to prevent

microbiological contamination of drug products purporting to be sterile, shall be established and followed.

Such procedures shall include validation of all aseptic and sterilization processes.

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Citations

The Code of Federal Regulations: § 820.70 (c), (d), (e) Production and process controls

(c) Environmental control. • Where environmental conditions could reasonably be expected to

have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions.

• Environmental control system(s) shall be periodically inspected to verify that the system, including necessary equipment, is adequate and functioning properly.

• These activities shall be documented and reviewed.

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Citations


(d) Personnel• Each manufacturer shall establish and maintain requirements for

the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality.

• The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual.

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Citations


(e) Contamination control. • Each manufacturer shall establish and maintain procedures to

prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.

regulatory considerations for environmental monitoring

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