Sterile Product Manufacturing - PowerPoint Presentation

Slide1

Sterile Product ManufacturingSlide2

IntroductionTo give an overview of the principles involved in the manufacture of sterile products

The overall objective is to produce product that has a high assurance of sterility (and which meets all other quality parameters)

This presentation:

Summarises the general approach

Gives a framework for other detailed guides on specific aspects of sterilisation & sterile manufacturing

Illustrates the underlying principles

Provides advice and gives recommendations.Slide3

General Principles of Sterile Manufacturing

Moist Heat Sterilization

Dry Heat Sterilization

Aseptic Processing

Environmental Monitoring

Ethylene Oxide Sterilization

Sterile FiltrationWater systems validationSterility testingRadiation SterilizationVisual InspectionSlide4

Fundamentals

Sterility is the absence of living organisms

This is an absolute definition

The probability of achieving sterility depends on the overall process

It is generally accepted that a terminally sterilized product should have a probability of non-sterility of less than 10

-6

(i.e., a lower probability than one in a million of having a non-sterile unit)This is often expressed as an SAL Sterility Assurance Level of 10

6

This is a worst-case figure (with a challenge more resistant than product

bioburden

). Real confidence levels are generally very much higher

A figure that has sometimes been quoted for aseptically filled product is probability of non-sterility of less than 10

-3

. However, this is harder to analyse as contamination does not follow a clear statistical distribution. Potential contamination sources are not randomly distributed.Slide5

Why Validate and Control?

The test for sterility cannot confirm that the whole batch is sterile

It is performed on a sample from a batch and has statistical limitations

It can miss contamination if only a proportion of units are non-sterile

It is thus necessary to recognize and understand every aspect that could lead to loss of sterility assurance

Such conditions should be prevented by the application of carefully designed barriers and/or control measures.Slide6

Development – Validation and Control

It is important that the product and process are designed to maximise sterility assurance

Wherever possible, the product should be developed to withstand sterilization in the final container

Once the product design is defined, a suitable production process must be developed

This is installed and validated

The process must then be tightly controlled to assure reliability and consistency.Slide7

Product Design Considerations

For New Products:

Define product and processing requirements

Consider stability of product to the sterilization conditions

Base the process on achieving the required sterility assurance level

Where possible choose terminal sterilization in final container

Define process flow and the important microbiological aspectsEnsure changes are subject to strict change controlFor reviewing existing (marketed) products:Establish the process description and assess in detail

Preferably, sterilization should be by

compendial

procedures

Where other procedures are registered, assess SAL

Where necessary (if existing SAL is too low) may need to improve process and maybe re-register

Require justification & validation.Slide8

Facility Design

Must be in compliance with company policies and procedures, for example:

Must minimise the risk of contamination at all critical stages

Required Grades of Clean Rooms : need to be appropriate for the process - e.g. for Terminal Sterilization or Aseptic Fill

Personnel Access and Material Flow

Restricted access, correct gowning

Materials flow, air locks, decontamination, segregationHVAC-SystemSegregation/Dedicated HVAC of correct standard

Requires control of Filtration/ΔP/Air Flow/Temp./Pressure/Humidity

Air flow patterns demonstrated

No sinks and drains in Zone A/B areas, air breaks to drains in others

Surfaces and ease of cleaning: smooth unbroken impervious surfacesSlide9

Cleaning and disinfection of the Facility

Cleaning and disinfection is important in environmental control

Efficacy needs to be validated

Validated procedures, conducted consistently

In class A & B areas, the cleaning and disinfectant materials must be sterilized

And need to minimise contamination risk in other areas

Operating procedures must include, at minimum:Preparation of cleaning materials (and sterilization if applicable)Exact procedure of cleaning & disinfection.

Responsibility & scheduling.

Type and concentration of detergents and disinfectants.

Type of cleaning tools.

Training is required for cleaning and disinfection of clean rooms

Routine decontamination using formaldehyde gas should be avoided.Slide10

Water

All water systems require good design and validation

Typically, for

pharmacopoeial

grades, validation includes

Two studies over a total of 4 weeks to assess against the acceptance criteria,

Additional 11 months to verify that the system remains under controlMust demonstrate consistent production of water of the required qualityPhysico

-chemical,

Microbiological,

Biological (

endotoxin

, where applicable)

Water systems must be regularly monitored following a defined written monitoring plan based on results of the validation studies.Slide11

Categories of Water

Water for Injections (WFI)

For

injectables

formulation

Final rinse water for product-contact items (for

injectables)Freshly prepared or from a validated hot (e.g., >75°C) storage /distribution system or otherwise protected from microbial contaminationHighly Purified Water (HPW)

To European Pharmacopoeia

Purified Water (PW)

For initial washing of product-contact items

Prepared, suitably stored and distributed to maintain quality and prevent microbiological proliferation, following the relevant company procedures.Slide12

Gases and Vacuum

Gases

Specification equivalent to the room air quality where it is to be used

In aseptic applications, gases are to be filter sterilized

Consider sterile filtering non-product contact gases for aseptic applications. (But, note safety considerations, e.g. avoidance of leakage)

All gas filters to be integrity tested on installation and at defined intervals

Vacuum SystemsSometimes used for cleaning and dust controlMay be mobile units, fitted with exhaust HEPA filtersOr may have central dust collection

On these, use dedicated vacuum pumps’ protected against back-flow

Design to prevent unprotected route into the aseptic suite.Slide13

Equipment (1)

Equipment Qualification

To include the critical aspects for sterile product processing

Qualification of critical aspects of moist heat sterilization, aseptic processing, dry heat sterilization etc.

Cleaning and Sanitization of Equipment

Equipment designed for easy cleaning and sanitization

For Terminal Sterilization applications, low microbial challenge. Where possible, critical surfaces should be sterilizedFor aseptic work, the critical (product contact) surfaces must be sterilized before use. In exceptional cases where this is not possible (e.g., some stopper bowls), they should be sanitized by a validated method

Cleaning validation must show effectiveness and absence of residues.Slide14

Equipment (2)

Equipment Sterilization and handling

Sterilization must follow a validated procedure

Aseptic processes designed to minimise aseptic assembly and intervention

Unavoidable aseptic assembly needs clear & precise procedures

Aseptic assembly must be simulated (worst-case) in media fill simulation trials

Sterilization In Place is a good method where possible – must be validated.Slide15

Personnel

Training - personnel appropriately trained for sterile processing, including assessment and documentation:

Basic GMP

Fundamentals of microbiology

Personal hygiene, health and cleanliness

Behaviour and aseptic working techniques

Gowning and entry proceduresCleaning and disinfectionSterilization procedures, validation and routine operation

Emergency procedures to protect product quality (e.g. loss of HVAC System, loss of power, equipment interventions etc.)

Personnel participating in aseptic processing must have practical training in aseptic techniques before doing aseptic manipulations

They must have participated in a successful media fill run.Slide16

Gowning and Aseptic Technique

Gowning

Personnel must correctly wear appropriate clean room garments

Detailed, easily understood, gowning procedure (preferably illustrated)

Aseptic Techniques

Personnel in the aseptic manufacturing area, must understand the principles of aseptic procedures

They must only be considered qualified after appropriate training, working under supervision and demonstration of competenceThe supervisor should observe technique & correct as necessaryAll personnel directly involved in aseptic processing must participate in a media fill at least once per year

Glove disinfection

Sterile disinfectants must be available (e.g., alcohol based)

Glove disinfection must be reasonably frequent, defined in SOP.Slide17

Environmental Monitoring (1)

The scope of environmental monitoring includes:

Non-viable particulates,

Viable (microbial) counts

Differential pressures

Temperatures

HumiditiesAir flowsSlide18

Environmental Monitoring (2)

Monitoring During Room Qualification

Operational Qualification (OQ) at rest conditions to verify operation

Performance Qualification (PQ) in worst case operational conditions

Action levels should meet USP or Euro GMP as applicable

Alert levels tight enough to detect deterioration, but not so tight that they become meaningless due to frequent transgression

PQ must cover a sufficient period to establish consistencyRoutine MonitoringEnsures area remains satisfactory. Results should be within alert levelResults above alert levels need review and perhaps corrective actions

Above action levels, must trigger appropriate actions (described in guide),

Results must be assessed for trends so that progressive or sudden changes in the results may be observed. This should be reviewed regularly.Slide19

Environmental Monitoring (3)

Deviation Reports and Failure Investigations

The data must be analysed

Where necessary further investigations initiated

Possible contamination sources to be assessed and, eliminated

Outcome and detail must be reported

Recommended Methods for Routine MonitoringPhysical measurements of the air supplyPhysical and microbiological monitoring of the environmentParticles (viable and non-viable) in the airMicro-organisms settling out of the air

Micro-organisms contaminating surfaces

Presence of micro-organisms on the hands and garments

Monitoring Plan

Defined monitoring plans: tests, locations, alert/action levels & frequencies

May contain details of water, compressed gas clean steam testing

A review of environmental data is a requirement for batch release.Slide20

Bioburden and Components

Active Ingredients,

Excipients

, Additives

All ingredients should have appropriate biological specifications

Any limitations to sterilization must be defined

Description of origin (e.g. virological / prion risk)

Materials Used in the Process

Where appropriate, determine

bioburden

(e.g., ion exchange materials)

Primary Packaging Components

Container and the closure and cleaning / sterilization to be clearly specified

Steps such as

siliconization

may need monitoring

If cleaning/sterilization is by supplier, same exigencies apply

Container-closure integrity

The integrity must be validated

Simulate, where appropriate: stress from processing

Method appropriate to container/closure systemSlide21

Weighing, Compounding and Sterilization

Weighing and compounding must be carried out in suitably classified rooms

Vessels must be cleaned, and sterilized or sanitised as appropriate and stored dry in a way to prevent microbial contamination

Storage of pre-sterilization intermediates to be controlled & time limited

Following aspects to be considered:

Pre-filtration

bioburden (filter sterilized material)Pre-sterilization bioburden

Appropriate in-process controls

Sterilization of product and product contact materials

Selection of a suitable sterilization protocol must be based on SAL

Method must also consider the stability of the product

Validation always required

Change control is vital; even apparently minor change must be assessedSlide22

Terminal Sterilization

Steam Sterilization

By far the most common method for aqueous-based pharmaceuticals

Preferred cycle is the

Pharm

Eur reference cycle is 15 minutes at 121°CThe sterilization cycle chosen must be compatible with product stabilitySterilization parameters clearly definedIn conjunction with other controls, the required SAL must be demonstrated

Validation to confirm sterilization conditions consistently throughout the load

Sterilization by Ionizing Radiation

Common for medical devices, but not for pharmaceuticals.

Pharm. Eur. reference condition, 25

KiloGray

(

kGy

), has been widely accepted. Other conditions may be used if validated and accepted by the regulator

Important to consider susceptibility of the product to radiation damage

Dry Heat Sterilization

Lower antimicrobial efficacy than moist heat, thus higher temperatures and/or longer exposures.

Pharm

Eur

reference cycle is 2 hours @ 160°C

Rarely used for terminal sterilization of pharmaceuticals; in rare cases heat resistant non-aqueous products may be terminally sterilized.Slide23

Sterilization of Items for Aseptic Fill (1)

Steam Sterilization

Widely used, but careful validation needed – particularly complex items

Broadly similar to terminal steam sterilization, but two aspects are critical

Quality of saturated steam

Removal of air and subsequent steam penetration

Sterilization by Ionizing RadiationMay be used for temperature sensitive primary packaging or componentsUsed for disposables for sterile areas and sterility testing areasValidation includes dosimetry

, - correct, even, irradiation of the items

Dry Heat Sterilization/

Depyrogenation

Sterilization/

depyrogenation

of heat resistant primary packaging materials

Pharm

Eur

notes that temperatures in excess of 220

o

C have been frequently used, the USP suggests 250 ± 15

o

C

Validation must include

endotoxin

challenge studies

Dry heat may be used to sterilize non-aqueous preparations (e.g. Ointment bases) at lower temperature/time relationships, without

depyrogenation

.Slide24

Sterilization of Items for Aseptic Fill (2)

Ethylene Oxide Sterilization

Quite widely used to sterilize heat labile components

European Pharmacopoeia and the European GMP guide indicate that this method should only be used where there is no suitable alternative

Hazardous - toxic, potentially carcinogenic, flammable, potentially explosive

Generally conducted by specialized contractors

There are strict regulatory limits on maximum permissible product residuesBulk packs for sterilization must be gas permeable, but sealed against microbial ingressSterilization must consider packaging, load pattern, gas penetration (ethylene oxide & water vapour), bulk pack integrityValidation and routine monitoring must include Biological indicators.Slide25

Sterilization by Filtration (Liquids)

Principle:

Contaminating organisms are not killed, but are retained on the filters. Any faults in the filter structure, may compromise this

Validation includes:

Retention of bacterial challenge: B.

diminuta

at 107 per cm2This is correlated with an integrity test valueValidation should address:Filter suitability - toxicity,

extractables

, shedding of particles

Adsorption of product

Compatibility with product solvents

The required filter size and suitability of the filtration equipment

Retention of

B.diminuta

in the actual product under process conditions

Parameters for the physical integrity test

Routine Filtration

Conducted in line with the validated parameters

Check integrity testing, process time, differential pressure, flow rates, sterilization and reuse of filters.Slide26

Performance Qualification of Aseptic Manufacturing

Based on simulating the risk of contamination in all aseptic operations

For a new process, a minimum of three consecutive satisfactory media filling trials

For aqueous liquid products, simulation trials use a liquid microbiological medium

For solid dosage forms, a powder ‘placebo’ is used, followed by aseptic reconstitution into a liquid microbiological medium

The following slide gives a general overview....Slide27

Aseptic Process Simulation

(Media Fill Trial)

Media Fill Trials (MFTs)

All process stages simulated as closely as possible

Particularly interventions and manual manipulations

Must follow routine procedures and include all interventions

Regular interventions simulated with the same frequency as actual processIn each case, the worst-case eventuality must be covered

Process must be successfully validated before product filling is permitted

Revalidation by media fill must be conducted every half year (each line)

Manufacturing Environment

Microbiological monitoring must be performed during the trial

Filling Conditions and Equipment

All according to routine operating conditions and at normal times of day

Containers must be passed through all stages.Slide28

Thank You

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