Manufacturing of Sterile Products Session 3 of 3-OA-13 May 2015

Manufacturing of Sterile Products

Session 3

Risk based Progressive Model to Assess

Facility & Operation

Presentation Focus

1. What is Risk

2. Risk Calculator

3. Risk Model for Aseptic Sterile Operations

4. Risk Model for Terminally sterilized Products

Closing Message

Right Tool for Right Work

Guenther Gapp & Peter Holzknecht

Risk Analysis of Sterile Production Plants: A New & Simple Workable Approach

PDA J Pharm Sci and Tech 2011

Process Understanding

Control what is critical

Process understanding as input to Risk Management

Identify Critical to Quality parameters

Improved Process Knowledge to Identify and Remove Sources of Variability

ICH Q9, Quality Risk Management

What does it mean?

What is it worth?

Where does it lead?


Severity

Probability Detectability

Detectable and controlled lionLess detectable & free small

snack

Which is Dangerous



Fall less frequently (1 time in a month)

Fall more frequently (10 times in a month)

Which is Dangerous


Combination of the probability of occurrence of

harm and the severity of that harm

Managing Risk is a Behavior

The

investigation of

risks

is at once a

scientific activity

and an

expression of

culture

Parameters for “calculating” Risk

• Past Probability

• Today Detectability

• FutureSeverity

T

I

M

E

Risk Priority Number

Risk Calculator

Risk Assessment Matrix

Severity

Probability

Frequent Likely Occasional Not often Unlikely

Catastrophic E E H H M

Critical E H H M L

Marginal H M M L L

Negligible M L L L L

Presentation Focus

Risk model for

Aseptic Sterile Operation

Raw Materials

Raw

Materials/

Component

Received Contaminated

Contaminated during sampling

Contaminated during storage

Personnel

Personnel

Inadequate hand sanitization

Poor personnel hygiene

Inadequate face, hair, cloth etc.

Personnel-Training

TrainingSOP

Program

Correct

Followed

Available

Personnel-Training

Training

Operators

ineffectively

trained

Evidence of training

Review of training proficiency

Proficiency not demonstrated

Training program not in place

Facilities

Facilities

Appropriateness of

constructions

materials

Difficult to sanitize

Particulate generation

Air Quality

compromised

Lack of Air Quality Control

HVAC-HEPA compromised

Facilities

Fa

cili

ties

Water quality

compromised

Generation sys compromised

Delivery hoses compromised

Source compromised

Dead Legs

Reverse inclines

Facilities

Facilities

Compressed gases compromised

Other water issues

Standing Water

Dripping Pipes

Cleaning/ Sanitization

Cle

an

ing

/ S

an

itiz

ati

on

Inadequate pest control

Ineffective sanitization agents Compatibility of agents

Lot to lot cleaning effectiveness

Carry over

Residual

Bio-burden

Contamination of cleaning implements

Resistant pattern against cleaning

Inadequate removal of visible debris

Process

Pro

cess

Transfer/

sampling issue

Sample hold compromised

Sampling error

Transportation compromised

Inadequate

separation betweenClean and dirty operations

Process

Pro

cess

Hold time is not

validated

Process hold time

Clean hold time

Dirty hold time

Inadequate protection uncontrolled environment

Presentation Focus

Risk model for

Terminal Sterilization Operation

Raw Materials (Non-Sterile)

Supplier audited by

others

Supplier approved

through your own audit

Batch wise incoming microbial count and endotoxin testing

• Appropriate frequency

• Lower frequency

• No testing

History and trends of incoming material

compiled and reviewed

Raw Materials (Non-Sterile)

Preparation of antibiotic/ micro-static material in Class D or lower room classification

Preparation of growth promoting material in Class C or lower room classification

Nature of material

Antibiotic Micro static Growth promoting

Filling/Sterilization Operations

Product undergoes a microbial filtration before filling

Clean room design and zoning concept

Filling in Class A or Class B or Class C

Unidirectional air flow above and/ or at critical locations (e.g. turntables, interventions..) or not

(turbulences or shadowing)

Optical impression of house keeping


Clean room

parameters appropriate

Non-viable particulate

count

Pressure

Air exchange rate

Humidity

Temperature


Alarm response for clean room parameters in place

Good alarm system for clean room parameters in place

Visual signal system in place


Smoke study video during

filling operations

demonstrate

Uniform air flow

Non-adequate air flow

No studies


Closed transport under controlled conditions through surrounding area

All interventions are documented

Transfer of material from surrounding area into filling area controlled

All heat stable equipment and material heat sterilized


Appropriate gowning concept

Personal airlock: the final stage should be the same as the surrounding filling area

Defined sanitization step while approaching of material to Class C and D from lower area


Validation of disinfection

Via carrier testSuspension

testingNone

Documentation of cleaning and disinfection procedures

Good Not good None


Non-viable particulate (NVP)measurements

according to respective clean room requirements

Periodical use of sporocidal disinfectants

for clean room and filling cabinet

Micro EM trends

Well-designed rationale micro environmental monitoring (EM)

system based on risk analysis

Trend of NVP


Placement of investigation procedure in case of EM failure

Verification of EM results of production or engineering by

Quality Department

Oversight of QA and QC on EM performed by production or

engineering

Characterization of isolates

Placement of corrective action procedure in case

of EM failure


Verification of EM results of production or

engineering by Quality Department

Oversight of QA and QC on EM performed by

production or engineering

Characterization of isolates

Placement of corrective action procedure in case of

EM failure

Placement of investigation procedure in case of EM

failure


Qualification or disqualification criteria for

personnel defined

Qualification of maintenance personnel and others

Rationale of the location of sampling point for NVP

monitoring

Continuous training program for operators

involved in sterile filling

Monitoring program of qualified operators by

QA during filling


Looping temperature in water for injection (WFI) system

Endotoxin level of primary packaging material

Assessment of the impact on sterility in case of change in

change control procedure

Filling

Validation of WFI testing methods

Point of sampling of WFI


Endotoxin level of primary packaging

material

Assessment of the impact on sterility in

case of change in change control procedure

Validation of WFI testing methods

Point of sampling of WFI

Looping temperature in water for injection (WFI) system


Investigation ability for excursions in water

system

Qualification of water system (12 month study)

On-line monitoring of WFI

Monitoring of Bio-burden prior to

sterilization process

Qualification of autoclave


Use of Biological Indicator and Temperature Mapping in

Requalification of Autoclave

Annual requalification of Steam Sterilization process for

specific product

Bio-burden testing of Micro Lab

Product Specific D Value determination for

qualification process

Qualification and Requalification of

Loading plan


Periodical Audit of Service Provider of Autoclave

Control of Cool Down Phase by WFI

Steam Sterilization effect study and Over Kill approach

Container Closure Integrity performance at

different air pressure

Validation of Sterility Test


Holding, line Clearance and possibility of mixing

Visual Inspection programme of Sterilized Product

Closing Message

The question isn’t whether we will have standards …

The question is how useful can we make standards

Manufacturing of Sterile Products Session 3 of 3-OA-13 May 2015

Leadership & Management

Transcript of Manufacturing of Sterile Products Session 3 of 3-OA-13 May 2015