Pharmex Training Workshop, Cairo, 19-21 October 2009

Design and qualification

of pharmaceutical cleanroom systems
for optimized domination of contamination risks

Part 3:
Cleanliness zoning concepts
and risk assessment

1
Part 3: Cleanliness zoning concepts
and risk assessment

Topics:

Cleanliness zoning concepts and policies

Risk priorities to address

Air cleanliness requirements for

• sterile products
• non-sterile products

Quality risk management: a new tool for assessing GMP compliance

Risk assessment: point of departure for quality risk management

The FMEA risk assessment procedure: how it works

Why formal risk assessment?

2
Requirement profile for clean facilities

Everything must fit together harmoniously:

Facility concept

Process technology

Layout of the production area, optimized regarding
• material flow
• personnel flow

Containment quality including leakage limits, for
• walls, ceiling, floors

Building infrastructure
• HVAC, air cleanliness and airflow pattern considerations
• process media systems and process media cleanliness

Safety considerations
3
Cleanliness zoning concepts:
decisive elements of quality risk management

Basic elements - 1

Quality philosophy of the company / group of companies

Applicable codes of regulations, standards, recommended practices

Cleanliness requirements of processes and products

Personnel safety and environmental considerations

Compilation of cleanliness zones required regarding

• Particles
• Micro-organisms

Identification of the appropriate air cleanliness class

for each process step
4
Cleanliness zoning concepts:
decisive elements of quality risk management

Basic elements - 2

Requirements for
• Facility layout
• Building infrastructure including HVAC
• Process technology
• Building and process automation
• Safety issues

Qualification concept

Maintenance, monitoring, requalification and change control

Operational aspects
• Personnel issues (behaviour, hygiene, garmenting, training)
• Visitor handling
• Cleaning, disinfection and pest control 5
Protection objectives

Process and product protection, subject to

• inspection by medicines control agencies (EMEA, FDA, others)

addressing product safety issues

Personnel protection
protection, subject to

• inspection by factory inspectorates

assessing the safety and well-being of the facility’s personnel

Environmental protection, subject to

• inspection by environmental control authorities

focussing upon risks to the outside population
caused by emissions from the facility
6
Minimum air cleanliness requirements
for pharmaceutical processing steps
(Source: GMP Guideline of the European Union and PIC/S:
Annex 1: Manufacture of sterile medicinal products)

A. Terminally sterilized products

Preparation of components and solutions:

normal risk: at least grade D

high or unusual risk: grade C

Filling:

normal risk: at least grade C

unusual risk:
• process area: grade A
• background: at least grade C

Preparation and filling of ointments, creams,

suspensions and emulsions: grade C
7
Minimum air cleanliness requirements
for pharmaceutical processing steps
(Source: GMP Guideline of the European Union and PIC/S:
Annex 1: Manufacture of sterile medicinal products)

B. Aseptic preparation - 1

Components after washing: at least grade D

Handling of sterile starting materials and components:

without sterilization or sterile filtration later in the process:

• process area: grade A
• background: grade B

Preparation of solutions:

with sterile filtration during the process: grade C

without sterile filtration:
• process area: grade A
• background: grade B
8
Minimum air cleanliness requirements
for pharmaceutical processing steps
(Source: GMP Guideline of the European Union and PIC/S:
Annex 1: Manufacture of sterile medicinal products)

B. Aseptic preparation - 2
Handling and filling:

with and without sterile filtration:
• process area: grade A
• background: grade B

Transfer of partially closed containers (e.g. into freeze-dryers)

and subsequent capping and crimping of vials:

without sealed transfer trays:
• transfer area: grade A
• background: grade B

Preparation and filling of ointments, creams, suspensions and emulsions

(without subsequent sterile filtration):
• work area: grade A
• background: grade B 9
 Examples of an unusual risk during processing
of terminally sterilized products

High risk of microbial contamination due to products

• actively supporting microbial growth

• requiring a long period between preparation
and terminal sterilization
• processed not mainly in closed vessels

High risk of contamination from the environment due to

• a slow filling operation

• wide-necked containers
• exposure to the environment for more than a few seconds
before sealing

10
 Microbiological limits
according to U.S. Pharmacopeia
Product category Total aerobic Specific
microbial count micro-organisms
Parenterals and other Absence of colony forming units
sterile products (CFU))
Products for ≤ 100 CFU / (g or ml) ≤ 10 yeasts and moulds /
topical application (g or ml)
no E. coli, no S. aureus,
no P. aeruginosa
Liquids for ≤ 100 CFU / (g or ml) ≤ 10 yeasts and moulds /
oral application (g or ml)
no E. coli,
no salmonella
Solids for ≤ 1 000 CFU / (g or ml) ≤ 100 yeasts and moulds /
oral application (g or ml)
no E. coli,
no salmonella
Products for ≤ 100 CFU / (g or ml) ≤ 10 yeasts and moulds /
rectal application (g or ml)
no E. coli, no S. aureus,
no P. aeruginosa
11
Typical quality risk management process
(Source: ICH Q9 Harmonized Tripartite Guideline)

12
ICH Q9: Some quality risk management tasks

Review of regulatory expectations and development of appropriate

company-internal quality management procedures

Identification of personnel training requirements for reliable control of

process risks

Identification, assessment and elimination of quality defects of

• products
• production systems comprising premises, production equipment
and infrastructure systems

Determination of frequency and scope of audits (internal and external)

Change management and change control

Facilitation of continuous improvement of processes during the entire

life cycle of products and facilities
13
Risk management methods and tools
(Source: ICH Q9 Harmonized Tripartite Guideline)

Failure Mode and Effects Analysis FMEA

Failure Mode, Effects and Criticality Analysis FMECA

Fault Tree Analysis FTA

Hazard Analysis and Critical Control Points HACCP

Hazard Operability Analysis HAZOP

Preliminary Hazard Analysis PHA

Risk ranking and filtering

14
FMEA risk assessment procedure
(FMEA = Failure Mode and Effects Analysis)

Point of departure: three risk dimensions:

• Probability of occurrence: O
• Relevance of risk: R
• Probability of detection: D

Quantify above risk classes into, for example, 5 risk levels, e.g.
• 1: Negligible risk
• 5: Very high risk

Calculate the risk assessment number RAN:

RAN = OxRxD

Assess requirement for action (minimum RAN to be predetermined):

• Example: RAN ≤ 15: no action; RAN ≥ 16: action required
15
 Examples for value scale options for assessing
the probability of occurrence O

Value Probability* Frequency* Frequency

1 ≤ 0.01 % max. every 10 000th time annually

2 ≤ 0,1 % max. every 1 000th time monthly

3 ≤ 1,0 % max. every 100th time weekly

4 ≤ 10 % max. every 10th time daily

5 ≤ 100 % almost always daily more than once

* if statistical data are available

16
 Value scale determinations
for assessing the relevance R of a risk

Value Relevance of risk (e.g. for quality, safety)

1 negligible
2 small
3 medium
4 big
5 very big

17
 Examples for value scale options for assessing
the probability of detection D

Value Probability* Frequency

1 ≤ 100 % almost always

2 ≤ 10 % frequently
3 ≤1% sometimes
4 ≤ 0,1 % rarely
5 ≤ 0,01 % never or nearly never

* if statistical data are available

18
Determinations regarding the Risk Assessment Number RAN
and the need for action

RAN value, e.g. Risk Actions

≤ 12 small none required

13 - 23 medium desirable
24 - 125 big necessary

19
Example of a FMEA risk assessment and action plan

Fault Leak in terminal supply air filter of a HEPA filter

ceiling for the establishment of unidirectional airflow
Cause Damage during transport, carelessness during
installation
Effect Local increase of particle concentrations, air
cleanliness class requirement possibly not met
Probability of occurrence O=4
Relevance R=4
Probability of discovery D=4
Risk assessment number RAN = 4 x 4 x 4 = 64 → Actions required
Actions Visual inspection after installation, followed by
installed filter leak test according to ISO 14644-3
Assessment of success of O = 1; R = 4; D = 1; → RANnew = 4 → no further
actions actions required

20