small-volume-parenteral basic requirement handout

7/16/2019 Small-Volume-parenteral Basic Requirement Handout

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Basic requirements for a

GMP conform small volumeparenteral production facility

Approach to PIC Standard


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Content: Introduction

Clean room classification requirements

Process equipment requirements HVAC + clean room requirements

Process utilities requirements

Monitoring and recording requirements

Qualification / validation requirements

Conclusion


Basic requirements for a GMP conform small volume parenteral production facility


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Introduction


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The product:

Pharmaceuticals for parenteral use, manufactured by:

None aseptic process (sterilisation within final container)

Aseptic process (sterile filtration 0,22m; before filling)

Aseptic process (from sampling up to primary packaging)



Introduction

The primary container:

Vials

Ampoules Syringes

Cartridges


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Introduction

The process (example syringes):

Aseptically manufactured hazy products

Aseptically manufactured clear watery products Aseptically manufactured lyophilised products

Aseptically powder filling

Aseptic products with additional microbial filtration (0,22m)

Final sterilised watery products

RISK

Class C Class B Class D Class E

Compounding

vessel

active ingredients and excipients

LAF

class A

LAF

class A

Mobile

vesselSterile filter

Prefilter

Caps

Stoppers

Primary

containers

Liquid and solid

Secondary packaging

Filling

Sterilizing

tunnel

Washing

machine

Inspection


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Clean room classification

requirements


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Adequate air ventilation, conditioning and filtration with a differential

pressure concept between the different hygienic zones

Control, monitoring and recording of the critical clean room conditions

(e.g. differential pressure, particles, temperature, humidity etc.)

All surfaces and materials used in the clean room area should meet

the requirements in terms of none viable particle emission, cleaning

and disinfection as well as in terms of avoiding conditions for

microbiological growth

Access control for entering the clean rooms

Access of material and personnel only thru defined air locks with

adequate cleaning or gowning procedures

Qualification of the clean room itself as well as the personnel working

in these rooms

Use of adequate clean room clothing as well as regular training of the

operators as well as maintenance staff and other people working

in the clean rooms

What characterises a pharmaceutical clean room:


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Clean room classification according to EU Guide and ISO:

Hygiene Zone A B C D

Main

activity

EU-GUIDE A B C D

ISO 14644-1 5 5 5 7 7 8 8

Particles/m3

Rest* Oper. Rest* Oper. Rest* Oper. Rest* Oper.

0.5 m


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Clean room classification (not official):Hygiene Zone O* E F

Activity Manufacturing of open,non-sterile products

Manufacturing with closedproduct(inspection, warehouse,secondary packaging etc.)

Non-manufacturing area:(Labs, QC, administration,workshops, engineering,canteen)

Particles/ m3

Rest** Operation Rest** Operation Rest** Operation

0.5 m


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Classification of activities / rooms:

Activity/roomNone aseptic process

(sterilization within final container)

Aseptic process

(sterile filtration before filling)

Aseptic process

(from sampling up to primary

packaging)

Weighing/sampling D + LF C + LF A in B

Raw material handling

(e.g. milling, sieving, mixing)D + LF C + LF A in B

Compounding D + LF C + LF A in B

Sterile filtration D + LF C* or A in B -

Washing + primary packaging of stoppers D + LF D + LF D + LF

Pre-washingof equipment in direct contact with the product

D D D

Last rinsing (WFI)

of equipment in direct contact with the productD + LF D + LF D + LF

Sterilization + depyrogenation of primary

packaging material, including transportA in D A in D A in D

Filling + stopper placement of open containers A in C A in B A in B

Transfer to freeze dryer - A in B A in B

Crimping D D + LF D + LF

Product sterilization E - -

Inspection of closed primary containers E E E

Secondary packaging E E E

Quality conttrol F F F

Workshop F F F

Product offices F (up to class D) F (up to class D) F (up to class D)

Canteen for eating and drinking F F F

* if closed system


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Process equipment

requirements


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Process equipment requirements

Process equipment has to meet the requirements of the product (physical

and chemical) and process in terms of e. g. performance, material

requirements, cleaning and sterilization requirements, control and recording

requirements as well as clean room requirements

Avoid technical area of process equipment within the clean room area

as far as possible

Take particular attention in the interfaces of process equipment, (to otherequipment, utilities, clean room etc). Interface engineering is essential

to avoid start up delays and additional costs

Basis for the order should be a approved User Requirement Specification

and a Technical Specification, nevertheless have regular visits at the

equipment supplier and do a factory acceptance test before shipment

to site Do not over design process equipment evaluate very clearly in the URS

to specify the essential requirements I terms of GMP compliance features,

performance features, material requirements etc.

The design of the equipment has to be user friendly, take attention to

ergonomics, change over procedures already during the design phase,

and consider this in the decision process for equipment selection

General issues to consider for the design of process equipment:


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Process equipment requirements

Microorganism

Polished stainless steel; Ra


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HVAC and clean room

requirements


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HVAC and clean room requirements

A GMP compliant environment in terms of particles, germs,

air changes, airflow and separation of different clean room classes

Avoiding a contamination of the manufactured product

(e.g. with particles, germs, cross-contamination, cleaning supplies, etc.)

That the physical environmental requirements of the product will be met

(e. g. temperature, humidity, illumination etc.)

Prevention of any effects caused by the manufactured product

to either personnel or environment (or both)

(e.g. hormone production, cytostatics production etc.)

That the staff is working in comfortable atmosphere

The HVAC system together with the clean room has to secure:


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100% fresh air unit:

Continuous operation with 100% fresh outside air:

Negative: - high energy costs

Positive: - best solution when working with high potent materials

mixed air unitsVariable amount of fresh outside air, adjustable based on the

requirement from 0 100 %

(usually designed for max. 20% fresh outside air)

Positive: Low energy costs

Negative: Not recommendable for solid processing or high potent

material

100% recirculation air units

100% recirculation of air, can only be used in terms of absence of people.

Mostly used in combination with above systems, e. g. laminar flow units

Positive: Very low energy costs

Negative: Not usable in rooms with operators (only partly e. g. LF)

Working principles of HVAC units:


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turbulent mixing system

(class B, C and D)laminar flow system

(vertical flow)(class A)

laminar flow system

(horizontal flow)(class A)

Airflow principles in the clean room:


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recommendations for HVAC systems:

official Standard Pharmaplan

A B C D O E F

Air changes/h 0,45m/s 20%* 20-60 20 10-15 5-15 5-10 3-10

Prefilter F7 + F9 F7 + F9 F7 + F9 F7 + F9 F7 + F9 F7 F7

Final filtering HEPA/H14 HEPA/H13 HEPA/H13 HEPA/H13***

Overpressure [Pa]Unidirectional

airflow +15** +15** +15** +15** 0 0

Floor exhaust X (X) - - - - -

Temperature [C] 19-21 19-21 19-26 19 - 26 19 - 26 19 - 30 19 - 30

rel. Humidity < 55% < 55% < 65% < 65% < 65% < 65% < 65%

* Sinking speed at low turbulence displacement stream

** 0.05 inch water column (FDA) ~12.7 Pa

*** Not officially required according to EU GMP Guide; Annex 1


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Example: Clean room design elements:


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Process utilities

requirements


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Fluids, steam or gasses which are:

- part of the product itself or

- directly in contact with the product or

- used to clean surfaces in the clean room, or for equipment cleaning

Process utilities:

Fluids:- Purified water (PW)

- Highly purified water (HPW)

- Water for Injection (WFI)

- Solvents

Gasses:- Compressed air

- Nitrogen, Oxygen

- Other gasses (e. g. Carbon dioxide etc.)

Steam:

- Clean steam


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Pharmaceutical water:

Purified water:EP (European Pharmacopea):

Purified Water is intended for use of manufacturing preparations that do

not have to be sterile or pyrogen free, unless otherwise explained and

authorised

USP (United States Pharmacopea):

Purified Water is intended for use as an ingredient of official

preparations and in tests and assays unless otherwise specified

Highly purified water:EP (European Pharmacopea):

Highly purified water is intended for preparation of pharmaceuticals

that need water of a high biological quality, except where water for injection

is necessary (e.g. ear or eye drops) Water for Injection:

EP (European Pharmacopea):

WFI is water, to be used for preparation of parenterals that use water

as solvent .

USP (United States Pharmacopea):

WFI is intended for use preparation of parenteral solutions


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* 1st supplement to USP 27: WFI is water purified by distillation or a purification process that isequivalent or superior to distillation in the removal of chemicals and micro organism

European requirements (EP / EMEA) US-FDA requirements (USP)

Purified Water WFI HPW Purified Water WFI

Production

by...

Ion exchange

Distillation

Reverse osmosis

Other suitable

methods

Distillation e.g. Double-

reverse- osmosis

in connection

with other

suitabletechniques such

as Ultra-filtration

and Electro -

Deionisation

Appropriate

process, e.g.

deionisation,

Ion-exchanger,

distillation,reverse osmosis

or other suitable

processes

Distillation or

Other suitable

process*

Produced

from...

Drinking water Drinking water

Purified water

Drinking water Drinking water Drinking water

Purified water

Monitoring Conductivity

TOC

Microbiological

Nitrat, Heavy

metals

Conductivity

TOC,

Endotoxine,

Microbiological

Conductivity

TOC

Endotoxine,

Microbiological

Conductivity

TOC

Microbiological

Conductivity

TOC

Endotoxine,

Microbiological

Generation of pharmaceutical water:


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Monitoring and recording

requirements


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Clean room and process equipment / utilities

All data which are considered to have an impact on the product quality

(GMP critical) have to be controlled, monitored and recorded such as:

differential room pressures, temperatures, conductivity, particles,

air speed, pressures etc.

Where possible sensors for control and recording should be

independent (e. g. double Pt 100 temperature sensors; 1 to control

the process and one to be directly recorded)

All sensors to be considered as GMP critical have to be calibrated on a

regular basis

The right approach to evaluate which sensor is GMP critical is normallydone within the risk analysis process (GMP risk analysis)

GMP requirements for monitoring and recording...


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Example: Paperless recorder

Comes with full CFR part 11 compliance, can be connected via Ethernet toa central computer or via flash card, also GMP relevant text strings can be

printed, no limitation in terms of printers to be connected to the PC. Internal

memory stores results before data transfer is successfully completed


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Qualification and validation

requirements


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Definition

EU-GMP-Guide, Glossary

Qualification

Action of proving that any equipment works correctly and actually leads to the

expected results. The word validation is sometimes widened to incorporate the

concept of qualification.

PIC-Document PI 006-1

Any aspect of, including significant changes to, the premises, the facilities, the

equipment or the processes, which may affect the quality of the product,

directly or indirectly, should be validated and qualified.



Qualification and validation requirements

Qualification provides documented evidence that equipment is

designed and works as it should:Qualification equipment-related

Validation provides documented evidence that processes lead to product

of the desired quality and safety:

Validation process-related


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EngineeringTransport /

Installation

Process

start up /

test runs

Process-

Optimi-

sation

FDS/DQ PV / CVPQIQFAT SAT/OQ

Detail RA

Change Control Procedure

Construction Commis-

sioning

URS

Basis RA

Re-Qual.

Routine

Production


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PIC/S, PI 006-1, Recommendations on Validation Master Plan,

Installation and Operational Qualification, Non-Sterile ProcessValidation, Cleaning Validation, Aug.2001:

The qualification and validation process should establish and provide

documentary evidence that:

2.3.1 The premises, the supporting utilities, the equipment and the

processes have been designed in accordance with the requirements ofGMP. This normally constitutes Design Qualification or DQ.

2.3.2 The premises, supporting utilities and the equipment have been

built and installed in compliance with their design specifications. This

constitutes Installation Qualification or IQ.

2.3.3 The premises, supporting utilities and the equipment operate inaccordance with their design specifications. This constitutes Operational

Qualification or OQ.

2.3.4 A specific process will consistently produce a product meeting its

predetermined specifications and quality attributes. This constitutes

Process Validation or PV. The term Performance Qualification

or PQ may be used also.


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briefly describe: why, what, by whom, how and when the validation isto be carried out

provide up to date information about the actual state of affairsrelating to validation

demonstrate the firms commitment to carry out adequate validation

Example: Validation Master Plan

Front Page

Introduction (Purpose, Target)

Validation Philosophy

Organisation

Project Description

Timetable and Capacity Plan

Risk Analysis

Qualification

Validation Change Control

Personnel Training

Annex


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EU Guide to Good Manufacturing Practice

Main Part: Chapters 5 + 6 Annex 11: Computerised Systems

Annex 15: Qualification and Validation

FDA Regulations

Guideline on General Principles of Process Validation, 1987

Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing,September 2004

FDA 21 CFR Parts 210 and 211: cGMP Amendment of Certain Requirementsfor Finished Pharmaceuticals, Proposed Rule; May 1996

Guides for Inspection

PIC

PIC/S-Document PI 006-1Validation Master Plan, Installation and Operational Qualification,

Non-sterile Process Validation, Cleaning Validation

PIC/S-Document PI 007-1Validation of Aseptic Processes

PIC/S-Document PI 014-1Isolators used for Aseptic Processing and Sterility Testing


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Conclusion


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Conclusion

The technical complexity of a project is driven mainly by the product, theprocess and the desired GMP compliance approach: (e. g. NaCl water

solution in ampoules heat sterilizable vs. cytotoxic solution containing

solvents to be freeze dried in vials). Therefore the technical solution

should consider this with the aim to keep it simple !

A GMP compliant plant these days does not automatically implement to

invest a lot of money. Local equipment in a well designed and kept

environment can be better than expensive 1st class European or

American equipment in a bad environment

A good engineering and risk assessment safes a lot of money without

lowering the overall quality standard

Documentation becomes more and more importance during official GMP

audit, therefore start from the beginning and implement a proper changecontrol procedure

Implement the adequate standard for equipment, clean room, utilities and

process equipment based on the GMP requirement and the risk ! Spend

your money smart !

Do from time to time an audit on site by a experienced third party in order

to identify GMP or design gaps and define correction measuresbefore official inspections

Some points to consider...

A h PIC S d d


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Conclusion

US-FDAGuidance for industry:

Sterile drug products produced by aseptic processing current good

manufacturing practice (Sept. 2004)

www.fda.gov EU

EC Guide to good manufacturing practice for medicinal products and activepharmaceutical ingredients (Annex 1)

www.emea.eu PIC

Guide to good manufacturing practice of medicinal products (July 2004)

www.picscheme.org

ISPEBaseline Guide: Pharmaceutical engineering guides for new and renovated

facilities; Volume 3 Sterile manufacturing facilities

www.ispe.org

Some of the most relevant guidelines...

A h t PIC St d d


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Conclusion

A h t PIC St d d


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Conclusion

small-volume-parenteral basic requirement handout

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