Dr. Leonard W.

Mestrandrea
Principal Consultant
MESTRANDREA CONSULTING LLC

Microbial Control Considerations

y Product
P d tD Development
l t
y Routine Monitoring
y Water systems and Usage
y Active Ingredients
y Equipment Design and Use Conditions
y Personnel
y Manufacturing Environment

1
Overview
y Significance of microorganisms in non-
sterile pharmaceutical products

y It is recognized that there is no current

regulatory requirement for microbial control
in the manufacture of non-sterile
pharmaceutical products

Overview (continuation)
y Guidance and Recommendations for
performing a microbiological assessment
considering a total program of facility,
material and personnel management
y Recommend a program of control for the
manufacturing environment rather than
control
t l by
b di
directt environmental
i t l monitoring
it i
of the manufacturing area.

2
 Compendia or Registered Drug Products
Requirement

Compendia
p Registered
g
Yes Test
Yes

Test as required No

Water Activity

LT 0.6 0.6 or more

Method Dev / Recovery Growth

Method Dev/Recovery

Test for Total Count, Yeast,

Mold and Objectionables
No test
No test

Packaging Components
Compendia or Registered
Requirement

Compendia Registered Yes Test

Yes No

Test as Required No Routine Micro Testing Recommended

No routine testing is recommended unless it is a regulatory commitment

3
 Water

y Requirements stated in FDA Guide to Inspections

of High Purity Water Systems, July, 1993

y USP34/NF 29 – Water for Pharmaceutical

Purposes

y APHA Methods for the Examination of Water &

Waste Water

Purpose

To describe Microbial Monitoring and Control

in Non-sterile Manufacturing Areas that
emphasizes a Risk Based Approach

4
 CFR Citation
211.110 Sampling and testing of in-process
materials and drug products
y To assure batch uniformity and integrity of drug
products, written procedures shall be established and
followed that describe the in-process controls and tests,
or examinations to be conducted on appropriate
samples of in-process materials of each batch. Such
control procedures shall be established to monitor the
output and to validate the performance of those
manufacturing processes that may be responsible for
causing variability in the characteristics of in-process
material and the drug product.

CFR Citation (continuation)

Such control procedures shall include, but are not limited
to the following
to, following, where appropriate:
y Tablet or capsule weight variation
y Disintegration time
y Adequacy of mixing to assure uniformity and
homogeneity
y Dissolution time and rate
y Clarity, completeness, or pH of solutions
y Bioburden Testing

5
 Approach

How do we effectively apply microbial control in

the manufacture of non-sterile products?
y Use HACCP to understand the process
y Define where microbial contamination could
occur
y Effectively determine the best control and
monitoring methods

Development of an Environmental
Monitoring Program Through the
Use of HACCP Risk Management
Process

6
 Presentation Overview
y Why Risk Based control
y Industry survey results
y Risk Assessment
y Aspects of Unclassified Manufacturing Areas
y Monitoring and Control
y Sampling Methods and Frequency
y Setting Alert and Action Guidelines
y Environmental Monitoring Program and
Response to Excursions

Why Risk Based Control?

y No well defined regulatory standards or guidance
exists
i t for
f the
th microbiological
i bi l i l control
t l off non-sterile
t il
pharmaceutical manufacturing environments
y Environmental control and monitoring of non-sterile
processes either range from non-existent to parallel
programs to aseptic processing
y Data generated from some programs may be of little
value
l ffor the
h controll off the
h microbiological
i bi l i l quality li off
non-sterile environments in which the product is
manufactured

7
 Why Risk Based Control?
y Surveys of environmental practices for
non-sterile sites showed a wide range of
monitoring practices:
y 1994 PhRMA Survey
y 1998 AAI Micro Seminar Survey
y 2002 Pharmaceutical Systems Inc
Inc. Survey
y 2006 PDA Survey

Survey Results
y Misapplication of EM monitoring as a means of
microbial and process control;
y Questions on how the data would be used;
y Questions on the interpretation of the data and
its significance to product quality and safety to
the consumer;
y Widespread variability in programs resulting in
confusion.

8
 Approach
So, how do we effectively apply microbial control
in the manufacture of non-sterile products?

One approach is to use a risk based approach to

understand the process, define where microbial
contamination could occur and effectively
determine the best control and monitoring
methods.

HACCP Risk Management

Process
y Describe each manufacturing
process/control area
y Develop process flow diagram
y Determine Critical Control
y Establish Environmental Monitoring
Procedures

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 Microbiological Assessment
Areas for Review
y Engineering control of the air system to those areas, e.g.
relative humidity, temperature, air changes, filter integrity
inspections, pressure differentials, etc.
y Product and material flow
y Personnel traffic flow
y P
Personnel l practices
ti and
d ttraining
i i
y Cleaning and maintenance measures
y Collection, transportation and storage of wastes

Points to Consider when

Performing a Risk Assessment
y Synthesis, isolation and final purification of the drug
substance
y Microbiological attributes of active pharmaceutical
ingredients
y Microbiological attributes of the pharmaceutical
p
excipients and inactive ingredients
g
y Inherent antimicrobial properties of the drug product
y The formulation of the drug product and hold point
storage conditions
y Water activity of the drug product

10
Points to Consider when
Performing a Risk Assessment
(
(continuation)
ti ti )
y Processing conditions for the drug product facility
y Equipment design
y Cleaning and sanitization
y Process water p
production,, storage,
g , distribution and
use
y Housekeeping and disinfection procedures
y Packaging of the drug product, with particular
attention to integrity and vapor barriers

Points to consider when

Performing a Risk assessment
(continuation)
y Storage conditions and packing of intermediates
and finished dosage forms
y Route of administration of the drug product
y Is the p
product to be used chronically
y or acutely
y
y Age and general health of the patient population
expected to use the drug product

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Risk Assessment
y The order of risk of pharmaceutical products
based on the invasiveness of the route of
administration:
y Injectable products (sterile)
y Ophthalmic products (sterile)
y Inhalation solutions (sterile)
y Metered-dose
Metered dose and dry powder inhalants
y Nasal sprays
y Otics
y Vaginal suppositories

Risk Assessment (continuation)

y Topicals
y Oral liquids (aqueous)
y Oral liquids (non-aqueous)
y Rectal suppositories
y Liquid-filled capsules
y Oral tablets and p
powder-filled capsules
p

12
 Non-Sterile Product Microbial
Influences

Important Aspects of Unclassified

Manufacturing Areas
y All walls, ceilings and floors should be constructed
with non-porous, cleanable materials;
y All processing, sampling and packaging areas should
be 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.

13
Gowning in Manufacturing Areas
Protective Clothing Operators in formulation
and packaging areas
Plant uniform or plant uniform with Yes
overall for higher risk product and
environment
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)

Environmental
Monitoring Decision
Tree

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 Monitoring

Monitoring is the act of conducting a

planned sequence of observations or
measurements of control parameters.

Monitoring (continued)
y Steps to establish monitoring procedures:
y Identify best monitoring procedure for
each Critical Control Point
y On-line Systems
y Off-line System
y Observational Procedures
y Sampling location
y Determine frequency of monitoring
y Determine procedures
y Identify responsibilities

15
 Microbiological Samplings
Methods
y Air Sampling:
y Active
y Passive
y Surface Sampling:
y Contact Plates
y Swabs
y Rinse Sampling

Setting Alert/Action Guidelines

y Develop Data Base
y Review on a monthly basis
y Analyze on a yearly basis
y Follow ISO Class 8 Clean Room criteria
as a bench mark for preliminary action
levels

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Overall Management of an
Environmental Monitoring
Program
y All equipment should be qualified
y Suitability of monitoring methods demonstrated
y Standard Operating Procedures written
y Pharmaceutical Operators trained
y Data Management Systems established.

Response to Environmental
Monitoring Excursions
y Review
R i microbial
i bi l quality
lit attributes
tt ib t off
pharmaceutical ingredients and process
equipment used to manufacture product.
y Review cleaning validation process.
y Review data to include isolate identification.
y Review products manufactured with implicated
equipment to determine its capacity to support
microbial growth.
y Review intended patient population

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 EM = Environmental Monitoring
Are manufacturing operations being 
performed?
YES NO

Are manufacturing operations No EM performed

performed in a controlled area?

NO YES

Are there control measures in Perform EM according to control

place to provide a cidal effect or level 3
present extraneous
contamination?

NO YES

Need to evaluate the process.

Not an acceptable practice No EM performed

Environmental Monitoring Frequency 
Example

Type of Sample Frequency Alert & Action Levels

Airborne All Sites – 1X Week

1X after sanitization
Surface program Levels to be
established
Personal Monitoring Not Applicable
Non-Viable
Non- 1X per year
Particulates

18
Questions ?

Thank You!

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