particle monitoring systems for pharmaceutical manufacturing … · monitored as part of an...

Particle

Monitoring

Systems for

Pharmaceutical

Manufacturing

Guidance

Outline

► Introduction

► Air Particle Monitoring to GMP Annex 1

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Why Do You Need to Take Particle Counts? Pharmaceutical Manufacturing MUST be Carried out in a Controlled

Environment

A Controlled Environment by Definition Requires Particle Control

Greatest Concern is for Viable Particles (Microorganisms) Particle Counts are Used to Demonstrate Environmental Control

GMP Requires Controlled Environments are First Certified THEN

Monitored as part of an Environmental Monitoring Program

The Extent of the Particle Monitoring is Dictated by the Intended Market, Risk Factors, the Type of Products Manufactured, the Manufacturing Process and the Class / Grade of the Controlled Environment

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Cleanroom Classification Testing ► ANY Cleanroom Must be Tested or “Validated” to a Standard

► This is the Formal Testing to a Cleanroom Performance Standard

► GMP regulations are NOT Cleanroom Standards, They are regulations.

They do not provide enough specifications for performance of Cleanrooms

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Air Particle Monitoring to GMP Annex 1

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

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General 1. The manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

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For the manufacture of sterile medicinal products there are 4 grades: Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

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Clean room and clean air device classification

4. Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1.

Classification should be clearly differentiated from operational process environmental monitoring.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

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Clean room and clean air device classification

The maximum permitted airborne particle concentration for each grade is given in the following table.

Maximum permitted number of particles per m3 equal to or greater than the tabulated size

At Rest Operational

Grade 0.5µm 5.0µm 0.5µm 5.0µm

A 3,520 20 3,520 20

B 3,520 29 352,000 2,900

C 352,000 2,900 3,520,000 29,000

D 3,520,000 29,000 Not Defined Not Defined

GMP Annex 1:Grade A Monitoring

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9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed.

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The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded.

GMP Annex 1:Grade A Monitoring

This Essentially Means Continuous Particle Counting without any Gaps in the Data Collection: 1 Minute Particle Counting Interval for Grade A is Proven Adequate. This allows alarm response to happen no more then 1 minute after an event, rather then waiting for a cubic meter to alarm (or shut off an alarm). Additionally systems can be configured with both 1 minute (ft³) and 35.3 minutes (M³) sample volumes / times.

GMP Annex 1: Grade B

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10. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones.

GMP Annex 1: Grade B

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The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.

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GMP Annex 1:Monitoring System

11. Airborne particle monitoring systems may consist of: ► Independent particle counters ► A network of sequentially accessed sampling points

connected by manifold to a single particle counter ► A combination of the two.

Particle Transport Loss

10 ft (3 Meters) ~ Loss of 20% 5µm particles

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

► Isokinetic sample heads should be used in unidirectional airflow systems

► Laminar Air Flow (unidirectional airflow) Systems Should Provide a Homogeneous air Speed in a Range of 0.36 – 0.54 m/s (70-110 ft/min)

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Sample Probes:

Annex 1 States “The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing.”

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Particle Sampling Design

ASTM F50: (Not ISO but Helps) For particles in the size range 0.1 µm to 2 µm in diameter and a SPC flow rate of 0.028 m³/min (1 ft³/min), a transit tube up to 30 m long can be used. For particles size range 2 µm to 10 µm, a maximum transit tube length of 3 m can be used.

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Particle Sampling Design

ASTM F50: (Not ISO but Helps) If a flexible transit tube is to be used, then no radius of curvature below 15 cm shall be used.

Probe With Curvature of 15

CM Radius

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System Design: Sample Locations Risk Assessment: Recommended Practice ► System design based upon a formal risk assessment

► Identify representative locations where the product is at the most risk of exposure to potential contamination from airborne particles

► Sample positions are then defined as close as is practicable to these representative locations.

► It is recommended that dedicated Remote particle counters are used with isokinetic probes in Grade A so that there is continuous recording and alarming of particle counts at each sampling location for the full duration of critical processing and set up.

Recommended Practice: Source PHSS Technical Monograph No. 16

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The risk assessment should take into account:

► All locations where there is a possibility of operator intervention

► The observed process over a suitable and significant time period

► Original Room Classification Data

► Areas where there are normally no interventions but sterile components / products are still potentially exposed to airborne particulate contamination due to abnormal interventions

for other reasons ► The Length of time sterile components are in the process

Recommended Practice: Source PHSS Technical Monograph No. 16

System Design: Sample Locations

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System Design: Grade A Sampling Probes

Probes should be located as lose to the exposed product or aseptic process as practically possible. US FDA recommends probes within 1 foot (30.4cm) of exposed product with the probe in the airflow. In the case of non-unidirectional airflow Then in a vertical orientation.

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System Design: Grade B Less frequent particle monitoring can be justified where restricted access barrier systems (RABS) or isolator technology is used compared with conventional cleanroom technology. It should be sufficient to check Grade B corridors and Grade B areas at least once during each shift using portable counters or a manifold system with full re-classification on a 12-monthly basis in accordance with ISO 14644-2.

Recommended Practice: Source PHSS Technical Monograph No. 16

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

► The Sample Sizes Taken for Monitoring Purposes Using Automated Systems Will Usually be a Function of the Sampling Rate of the System Used.

► It is Not Necessary for the Sample Volume to be the Same as That Used for Formal Classification of Cleanrooms and Clean Air Devices.

1 ft

1 ft

1 M

1 M

Cubic Meter Cubic

Foot 1 Meter3 = 35.3Feet3

1 ft

1 M

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System Design: Grade C & D Particle monitoring in Grade C and D areas Portable counters or manifold systems are considered suitable for monitoring Grade C and D areas. Annex 1 states: 'The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operation carried out, but the recommended clean-up period of 15 - 20 minutes should be attained.

Recommended Practice: Source PHSS Technical Monograph No. 16

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Certification to 14644-1

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Monitoring Points

Monitoring Based Upon

Risk may require the

following

Where to Monitor

Monitor Critical Locations The Point of Fill

Component Hopper

Inspection Hatches

Descrambler Tables

Stoppering and Capping Stations

Loading of Freeze Dryers

Unloading of Sterilized Components

Interfaces Between Equipment and Grade A Area

Isolator Transfer Devices

Aseptic Manipulations

Operator Interventions 28

System Design: Locations

Additional Information

► Current Good Manufacturing Practice (cGMP)

21 CFR parts 210 & 211 http://www.fda.gov/cder/dmpq/cgmpregs.htm

► Guidance for Industry Sterile Drug Products Produced by

Aseptic Processing http://www.fda.gov/cber/gdlns/steraseptic.pdf

► EU Volume 4 - Medicinal Products for Human and Veterinary

Use : Good Manufacturing Practice (of Note)

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev4.htm

► Annex 1: Manufacture of Sterile Medicinal Products

► Annex 11: Computerized Systems

► PIC/s Annex 1

► WHO GMP

►Electronic Records; Electronic Signatures:

21 CFR Part 11 – FDA http://www.fda.gov/ora/compliance_ref/part11/

►GAMP 4 & 5 – ISPE http://www.ispe.org

►ASTM E2500-07: Standard Guide for Specification, Design, and Verification of

Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment

►ISPE Guide for validation of Process control systems

►ISO 14644-1: Cleanrooms and associated controlled environments -- Part 1:

Classification of air cleanliness

►ISO 14644-2: Cleanrooms and associated controlled environments -- Part 2:

Specifications for testing and monitoring to prove continued compliance

Additional Information

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PHSS Technical Monograph No16: Best Practice for Particle Monitoring in Pharmaceutical Facilities (June 2008) Specific advice on non-viable particle monitoring systems used in pharmaceutical facilities governed by EU GMP Annex 1, 2008.

Best Practice Document

Special Interest Group Companies AstraZeneca Bio Products Boehringer-Ingelheim Boots Contract Manufacturing Cardinal Health GlaxoSmithKline Hach Ultra Analytics Ipsen Biopharm Particle Measurement Techniques Wyeth MHRA Regulatory Inspectors (EMEA) Contributing Materials and Diagrams Lighthouse Worldwide Solutions Facility Monitoring Systems Particle Measuring Systems 31

Summary Pharmaceutical Manufacturing MUST be Carried out in a Controlled Environment

Greatest Concern is for Viable Particles (Microorganisms) Particle Counts are Used to Demonstrate Environmental Control

GMP Requires Controlled Environments are First Certified THEN Monitored as

part of an Environmental Monitoring Program

The Extent of the Particle Monitoring is Dictated by the Intended Market, Risk Factors, the Type of Products Manufactured, the Manufacturing Process and the Class / Grade of the Controlled Environment

Real time particle counting is required for Grade A aseptic manufacturing

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ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Grade Examples of operations for Terminally Sterilized products.

A Filling of products, when unusually at risk

C Preparation of solutions, when unusually at risk. Filling of products

D Preparation of solutions and components for subsequent filling

Grade Examples of operations for Aseptic Preparations.

A Aseptic preparation and filling.

B Background of Grade A

C Preparation of solutions to be filtered.

D Handling of components after washing.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

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Principle The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

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Note: This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards.

ISO 14644-1: Classification Testing ISO 14644-2: Testing for Continued Compliance with -1 ISO 14644-3: Test Methods ISO 14698-1 & 2 Microbial

5. For classification purposes in Grade A zones, a minimum sample volume of 1m³should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 µm.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Sample Volumes per ISO 14644-1 ► ISO 14644-1 B.4.2.1: ”At each sample location, sample a sufficient volume of

air that a minimum of 20 particles would be detected if the particle concentration for the largest considered particle were at the class limit for the designated ISO Class”

Vs is the minimum Sample Volume Per Location (in Liters) Cn,m is the class limit (particles / M3 ) for the largest considered particle size specified for the relevant class 20 is the defined number of particles that could be counted if the particle concentration were at the class limit

B.4.2.2 “The Volume Sampled at Each Location Must be at Least 2 Liters, With

a Minimum Sample Time at Each Location of 1 Minute”

Vs = 20_ X 1000

Cn,m

At Rest

Operational

Grade

0.5µm

5.0µm

Minimum Sample Volume

0.5µm

5.0µm

Minimum Sample Volume

A 3520 20 1000 3520 20 1000

B 3520 29 690 352,000 2900 7

C 352,000 2900 7 3,520,000 29,000 2

D 3,520,000 29,000 2 Not Defined

Not Defined

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Only Grade A Requires 1000 Liters (1M3) Sampling

What Particle Counter Flow Rate?

► You Can, but keep in mind, SINGLE SAMPLE VOLUME! ► Grade A: Single Sample Volume of 1 M³@ 2.83 L/ min flow = 383.35 min(~6 Hours) ► Grade B: in Operation (& C at Rest) Single Sample Volume 7 L @ 2.83 L/ min flow = 4.17 Minutes

► There is no restrictions in ISO or GMP. However one could argue Annex 1 wording “suitable sample size”. 1 CFM for monitoring is the most common.

► UNFOUNDED, NOT a Regulation, BUT IT DOES SAVE TIME!

► Single Sample Volume is SINGLE Sample Volume (when CERTIFYING)

Misconceptions about Particle Counter Flow Rates ► “They Say” You Cant use a Handheld to Certify a Cleanroom

► “They Say” You Cant Monitor at 0.1 CFM

► “They Say” You Have to have a 100 LPM Particle Counter for Testing Grade A Environments

► “They Say” You can Take 36(1 ft³/min) Samples and Total them for 1 M³

For classification purposes ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0µm in remote sampling systems with long lengths of tubing. Isokinetic sample heads should be used in unidirectional airflow systems.

ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Is this Best Practice?

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Example Locations

Blue = Grade A Yellow = Grade B 1: Exit of Sterilization Tunnel (Accumulator)

2: Point of Fill

3: Stopper Hopper

4: Stopper

5: Accumulator for Partially Stoppered Vials

6: Lyophilization

7: Grade B Background

8: Autoclave

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System Design: Grade C & D All Grade C and D areas must be monitored at intervals to be determined by a risk assessment. Grade C process areas should be monitored at more frequent intervals than less critical areas such as corridors, changing rooms and grade D areas. Re-classification of all areas should be conducted at intervals in accordance with ISO 14644-2.

Recommended Practice: Source PHSS Technical Monograph No. 16