04 Non SterileEMProgram

7/29/2019 04 Non SterileEMProgram

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Dr. Leonard W. Mestrandrea

Principal Consultant

MESTRANDREA CONSULTING LLC

Microbial Control Considerations

y ro uc eve opmenyRoutine MonitoringyWater systems and UsageyActive Ingredientsy Equipment Design and Use Conditionsy PersonnelyManufacturing Environment


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Overview

y Significance of microorganisms in non-sterile harmaceutical roducts

y It is recognized that there is no currentregulatory requirement for microbial controlin the manufacture of non-sterileharmaceutical roducts

Overview (continuation)

y Guidance and Recommendations forerformin a microbiolo ical assessment

considering a total program of facility,material and personnel management

y Recommend a program of control for themanufacturing environment rather than

con ro y rec envronmen a mon orngof the manufacturing area.


3/19

Drug ProductsCompendia or RegisteredRequirementRe isteredCom endia

Yes Test

No

Water Activity

LT 0.6 0.6 or more

Yes

Test as required

Method Dev/RecoveryMethod Dev / Recovery Growth

Test for Total Count, Yeast,Mold and Objectionables

No testNo test

Packaging Components

Requirement

Yes Test

No

RegisteredCompendia

Yes

No routine testing is recommended unless it is a regulatory commitment

No Routine Micro Testing RecommendedTest as Required


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Water

y Requirements stated in FDA Guide to Inspectionsof High Purity Water Systems, J uly, 1993

y USP34/NF 29 Water for PharmaceuticalPurposes

y APHA Methods for the Examination of Water &

Waste Water

Purpose

To describe Microbial Monitoring and Controlin Non-sterile Manufacturing Areas thatemphasizes a Risk Based Approach


5/19

CFR Citation211.110 Sampling and testing of in-process

materials and drug products

y To assure batch uniformity and integrity of drugproducts, written procedures shall be established andfollowed that describe the in-process controls and tests,or examinations to be conducted on appropriatesamples of in-process materials of each batch. Suchcontrol procedures shall be established to monitor theoutput and to validate the performance of thosemanufacturing processes that may be responsible forcausing variability in the characteristics of in-processmaterial and the drug product.

CFR Citation (continuation)Such control procedures shall include, but are not limited

, ,

yTablet or capsule weight variation

y Disintegration time

y Adequacy of mixing to assure uniformity andhomogeneity

y Dissolution time and rate

y Clarity, completeness, or pH of solutions

y Bioburden Testing


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Approach

the manufacture of non-sterile products?

y Use HACCP to understand the process

y Define where microbial contamination couldoccur

monitoring methods

Monitoring Program Through the

Use of HACCP Risk Management

Process


7/19

Presentation Overviewy Why Risk Based control

y Risk Assessment

y Aspects of Unclassified Manufacturing Areas

y Monitoring and Control

y Sampling Methods and Frequency

y

y Environmental Monitoring Program andResponse to Excursions

Why Risk Based Control?

y No well defined regulatory standards or guidanceexsts or t e mcro o ogca contro o non-ster epharmaceutical manufacturing environments

y Environmental control and monitoring of non-sterileprocesses either range from non-existent to parallelprograms to aseptic processing

y Data generated from some programs may be of little

va ue or t e contro o t e mcro o ogca qua ty onon-sterile environments in which the product ismanufactured


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Why Risk Based Control?y Surveys of environmental practices for

non-sterile sites showed a wide range ofmonitoring practices:y 1994 PhRMA Survey

y 1998 AAI Micro Seminar Survey

y .

y 2006 PDA Survey

Survey Resultsy Misapplication of EM monitoring as a means of

microbial and rocess control

y Questions on how the data would be used;

y Questions on the interpretation of the data andits significance to product quality and safety tothe consumer;

y Widespread variability in programs resulting in

confusion.


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ApproachSo how do we effectivel a l microbial controlin the manufacture of non-sterile products?

One approach is to use a risk based approach tounderstand the process, define where microbialcontamination could occur andeffectiveldetermine the best control and monitoring

methods.

HACCP Risk ManagementProcess

yDescribe each manufacturingprocess/control area

yDevelop process flow diagram

yDetermine Critical Control

y Establish Environmental MonitoringProcedures


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Microbiological AssessmentAreas for Reviewy Engineering control of the air system to those areas, e.g.

relative humidity, temperature, air changes, filter integrityinspections, pressure differentials, etc.

y Product and material flow

y Personnel traffic flow

y ersonne prac ces an ra nng

y Cleaning and maintenance measures

y Collection, transportation and storage of wastes

Points to Consider whenPerforming a Risk Assessment

y Synthesis, isolation and final purification of the drugsubstance

y Microbiological attributes of active pharmaceuticalingredients

y Microbiological attributes of the pharmaceuticalexci ients and inactive in redients

y Inherent antimicrobial properties of the drug product

y The formulation of the drug product and hold pointstorage conditions

y Water activity of the drug product


11/19

Points to Consider whenPerforming a Risk Assessmentcon nua on

y Processing conditions for the drug product facility

y Equipment design

y Cleaning and sanitization

y Process water production, storage, distribution anduse

y Housekeeping and disinfection proceduresy Packaging of the drug product, with particular

attention to integrity and vapor barriers

Points to consider whenPerforming a Risk assessment

y Storage conditions and packing of intermediatesand finished dosage forms

y Route of administration of the drug product

y Is the product to be used chronically or acutely

y Age and general health of the patient populationexpected to use the drug product


12/19

Risk AssessmentyThe order of risk of pharmaceutical products

administration:

y Injectable products (sterile)

y Ophthalmic products (sterile)

y Inhalation solutions (sterile)

y e ere - ose an ry pow er n a an s

y Nasal sprays

y Otics

y Vaginal suppositories

Risk Assessment (continuation)

yTopicals

yOral liquids (aqueous)

yOral liquids (non-aqueous)

yRectal suppositories

yLiquid-filled capsules

yOral tablets and powder-filled capsules


13/19

Non-Sterile Product Microbial

Influences

Important Aspects of UnclassifiedManufacturing Areas

y All walls, ceilings and floors should be constructedwith non-porous, cleanable materials;

y All processing, sampling and packaging areas shouldbe temperature and humidity controlled;

y All rooms used for manufacturing should be positive

to surrounding areas;y Air handling systems should contain centralized

HEPA or ASHRAE filters at the supply.


14/19

Gowning in Manufacturing AreasProtective Clothing Operators in formulation

Plant uniform or plant uniform withoverall for higher risk product and

environment

Yes

Hair/beard covering Yes

Safety glasses Yes

Dedicated shoes or shoe coverings Yes

Gloves Yes (if in direct product contact)

Face Masks Yes (if in direct product contact)

Monitoring Decision

Tree


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Monitoring

planned sequence of observations or

measurements of control parameters.

Monitoring (continued)y Steps to establish monitoring procedures:

each Critical Control Point

y On-line Systems

y Off-line System

y Observational Procedures

y Determine frequency of monitoring

y Determine procedures

y Identify responsibilities


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Microbiological SamplingsMethods

y Air Sampling:

y Active

y Passive

y Surface Sam lin :

y Contact Plates

y Swabs

y Rinse Sampling

Setting Alert/Action Guidelines

yDevelop Data Base

y Review on a monthly basis

y Analyze on a yearly basis

y Follow ISO Class 8 Clean Room criteriaas a bench mark for preliminary action


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Overall Management of anEnvironmental MonitoringProgram

y All equipment should be qualified

y Suitability of monitoring methods demonstrated

y Standard O eratin Procedures written

y Pharmaceutical Operators trained

y Data Management Systems established.

Response to EnvironmentalMonitoring Excursions

y evew mcro a qua y a r u es opharmaceutical ingredients and processequipment used to manufacture product.

y Review cleaning validation process.

y Review data to include isolate identification.

y equipment to determine its capacity to supportmicrobial growth.

y Review intended patient population


18/19

EM=EnvironmentalMonitoringAremanufacturingoperationsbeing

performed?NOYES

No EM performedAre manufacturing operationsperformed in a controlled area?

Are there control measures inplace to provide a cidal effect or

present extraneous

Perform EM according to controllevel 3

NO YES

Need to evaluate the process.Not an acceptable practice

NO YES

No EM performed

EnvironmentalMonitoringFrequencyExample

Type of SampleType of Sample FrequencyFrequency Alert & Action LevelsAlert & Action Levels

AirborneAirborne All SitesAll Sites 1X Week1X Week

Levels to beLevels to be

establishedestablishedSurfaceSurface

1X after sanitization1X after sanitization

programprogram

Personal MonitoringPersonal Monitoring Not ApplicableNot Applicable

NonNon--ViableViable

ParticulatesParticulates

1X per year1X per year


19/19

Questions ?

Thank You!

04 Non SterileEMProgram

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