#7 ispe environmental monitoring

7/23/2019 #7 ISPE Environmental Monitoring

1/40

Environmental MonitoringR Raghunandanan, Mumbai

Director ISPE India26th February 2011


2/40

26-02-2011 [email protected]

Introduction

Agenda


3/40


All the factors impacting quality and

safety of pharmaceutical products

Facility

Utilities

Machines

Personnel

Environment includes


4/40


GMP requirement

Facilities are designed to protect products from

contamination or deterioration

Facility must operate to meet the design

criteria

Only routine monitoring can prove that

facilities are functioning as designed.

Why environmental monitoring is

important


5/40


Regulatory Requirements, US FDA Microbiological control of drug manufacturing

areas: Statutory requirement as per 21 CFR 211 as

stated in Sections 211.46, 211.56, and 211.113 211 CFR 211.46, Ventilation, air filtration, air

heating and cooling:

Adequate control over microorganisms, dust,

humidity and temperature.

Pre filters and particulate matter air filters for air

supplies to production areas


important


6/40


Regulatory Requirements EM is a requirement of GMP as per WHO, MHRA,

MCC,TGA etc too.

Schedule M requirements Sec 8.2.1. The licensee shall prevent mix-up and

cross-contamination of drug material and drugproduct (from environmental dust) by proper air-

handling system, pressure differential, segregation,status labeling and cleaning. Proper records andStandard Operating Procedures thereof shall bemaintained.


important


7/40


Schedule M requirement

All environmental parameters listed under para

3.1 to 3.10 shall be verified and established at

the time of installation and thereafter

monitored at periodic intervals. The

recommended frequencies of periodic

monitoring shall be as follows :-


important


8/40


Schedule M requirement - recommended frequencies

(a) Particulate monitoring in air 6 Monthly.

(b) HEPA filter integrity testing (smoke testing) Yearly

(c) Air change rates 6 Monthly.(d) Air pressure differentials Daily.

(e) Temperature and humidity Daily

(f) Microbiological monitoring by settle plates and/or

swabs in aseptic areas - daily, and at decreased

frequency in other areas


important


9/40


Product deterioration Microbiological deterioration

Thermal deterioration

Humidity induced deterioration Product contamination

Particulate contamination

Cross contamination Increased bio-burden

Sterility failures

What impacts from environment


10/40


Product exposed areasAseptic preparation

Aseptic filling, blending

Preparatory areasSolution preparation

Component preparation

General areasComponent washing

Different environments


11/40


Non-viable air monitoring (particulates) Viable air monitoring (microbiological)

Surface monitoring (facility and equipment)

Personnel monitoring (garments & gloves) Temperature and humidity

Pressure differentials (p)

Gases and other utilities (including water) Disinfectants

Detergents and washing agents

What need to be monitored


12/40


Different classes of environments

EUGrade

ISO Class Class US FEDSTD

A 5 100 M 3.5

B 6 1000 M 4.5C 7 10,000 M 5.5

D 8 100,000 M 6.5

(US FED STD now replaced by ISO 14644-1 though

we frequently use the terminology Class 100 etc.)


13/40


Available standards and guidance

EU Annex 1, 2008 USP 32, General Chapter

ISO 14644

Schedule M of D&C Act and Rules of India

Guidance for industry, US FDA Sterile DrugProducts produced by Aseptic Processing-Sept

2004

21 CFR Part 211.42

21 CFR Part 211.46

(and others)


14/40


Available standards and guidance

It is important to remember that

All standards are not exactly identical

Manufacturer to follow the market

requirements as a minimum

You are free to have tighter in-house

standards


15/40


Area particulates (non-viable) EU Annex 1

Maximum no of particles per cubic meter

At rest In Operation

Grade 0.5

micron

5.0

micron

0.5

micron

5.0

micron

A 3520 20 3520 20

B 3520 29 352,000 2900

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

D 3,520,000 29,000 Not

defined

Not

defined


16/40


At rest and In Operation At rest

Air flow is ON

Equipment installed but not in use

No personnel in the area

In Operation

Air flow is ON

Equipment in operation (sometimes

simulated)

Specified no. of personnel in the area

Define these for each clean room


17/40


Microbiological monitoring standards

(EU Annex 1)

Limits for microbial contamination

Grade Air sample

Cfu/m3Settle plate

Cfu/4 Hrs

Contact

plate

Cfu/plate

Glove

print

Cfu/glove

A


18/40


Define Your Monitoring philosophy

Reduction of risk to patients

High confidence levels of sterility assurance

A systematic and risk based approach of

monitoring Investigation linked to Corrective and

Preventive Actions

Make assessments through trending theresults


19/40


Carry out risk assessment

Carry out a risk assessment based on

Type of product manufactured

Type and age of facility

Type and age of machinery Extent and type of containment used

Document the rationale based on the risk

assessment Periodically review the rationale and update

monitoring levels


20/40


Essentials of monitoring

programme

Should be capable of detecting an adverse

drift in a timely manner

This only will facilitate meaningful and

effective corrective actions

The programme should be facility specific

The manufacturer should develop, initiate,

implement and document a monitoringprogram meeting these essentials


21/40


SOP for environmental monitoring (i)

Detailed SOP for EM is one of the first steps and the

SOP to include

Reference to risk assessment

Responsibilities of various functions Locations of monitoring (drawing etc.),

document rationale

Sampling and testing methods, sample sizes

Specific sampling equipment and

techniques


22/40


SOP for environmental monitoring (ii)

Detailed SOP for EM to include

Frequency and time of sampling

Alert and action levels

Documentation and periodic reviews

Trending of results

Notification to all concerned duringexcursions


23/40


Need for trained personnel

Personnel involved in EM should

Be adequately qualified

Be experienced and trained

Know the local regulatory requirements

Know how to handle excursions

Have investigational skills


24/40


Area monitoring non-viable

Particulates monitoring required for all cleanrooms

During qualification

As part of routine review

Particulates equal to or greater than 0.5m

and 5.0m must be quantified

Samples must be at least one cubic meter involume (see ISO 14644-1)


25/40


Grade A monitoring - non-viable

Continuous monitoring of particulates in GradeA zones during preparation and operation

Continuous monitoring of particulates in GradeB is recommended

Point of fill monitored within 30 cm during

operation


26/40


Grade A monitoring - non-viable

Where particles are generated during operationuse simulated conditions (e.g. powder filling)

Rationale for simulated conditions should be

justified and documented


27/40


Area monitoring viable SOP to include additional details for

Media requirements, growth promotion tests

Need for neutralizers if any

Incubation requirements (time & temp)

Identification of organisms recovered

Precautions to avoid contamination during

and after monitoring (e.g.: use of contact

plates) Monitoring for anaerobic organisms at

defined intervals


28/40


Surface monitoring (i)

Surface monitoring involves sampling varioussurfaces for microbiological quality

Product contact surfaces, floors, walls, and

equipment should be tested on a regular basis Contact plates and/or swabs are the choice


29/40


Surface monitoring (ii)

Contact plates for smooth and easy to samplesurfaces

Swabs for difficult to sample surfaces

Helpful to assess Cleaning efficacy

Contamination potentials

Recovery studies need to be done


30/40


Personnel monitoring (i)

Personnel significantly affect the quality of theenvironment

Maintain contamination-free gloves and gowns

throughout operations Monitoring of each operator's gloves and

garments at exit

When exceed established levels or show anadverse trend, carry out investigation


31/40


Personnel monitoring (ii)

Follow-up actions shall include

Increased sampling

Increased observation of aseptic behavior

Retraining

Gowning re-qualification

Shifting the individual to other operations


32/40


Personnel monitoring (iii)

Trends from daily monitoring of personnel canprovide important information indicating possible

routes of contamination

Adequacy of personnel practices and training

shall be routinely reviewed


33/40


Temperature & humidity levels

Define product specific requirements

When exceeded assess impact on product

quality and patient safety

Understand regulatory requirements

Employ automated monitoring techniques

where possible

Alarms and notifications when limits are

exceeded


34/40


Setting alert and action levels

This is driven by

Product specific requirements

Regulatory requirements

Market requirements (customer market)

Findings during initial qualification

Arising out of trend analysis


35/40


Trend analysis

Monitoring trends provide assurance

That facility is under control

That practices are acceptable

Trends change when changes are made to

facility or practices

Trends help updating alert and action levels

and also frequencies


36/40


Dealing with excursions

Notification to all concerned Investigation to commence

Root cause identification

Interview personnel involved

Impact assessment on various batches

Remedial actions

Corrective and preventive actions


37/40


Corrective & Preventive Actions

CAPA should be agreed and documented Changes may be required to

Facility, HVAC system

Equipment, containment, barrier systemsWays of working

Training to personnel

CAPA should be progressed and closed


38/40


EM and batch release

EM data should be reviewed before release ofbatches of sterile products

Any excursions must be investigated and actions

completed before batch release Batches prior to and post to the excursions

should also be included in the investigations


39/40


Remember

A well-designed facility without

proper environmental monitoring

is nothing more than

an ill-designed facility


40/40

26-02-2011 [email protected] 40

Questions

#7 ispe environmental monitoring

Documents