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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
Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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)
Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Introduction
The primary container:
Vials
Ampoules Syringes
Cartridges
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Clean room classification
requirements
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Clean room classification requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Clean room classification requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Clean room classification requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Clean room classification requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Process equipment
requirements
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Process equipment requirements
Microorganism
Polished stainless steel; Ra
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
HVAC and clean room
requirements
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
HVAC and clean room requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
HVAC and clean room requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
HVAC and clean room requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
HVAC and clean room requirements
Example: Clean room design elements:
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Process utilities
requirements
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Process utilities requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Process utilities requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Process utilities requirements
* 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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Monitoring and recording
requirements
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Monitoring and recording requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Monitoring and recording requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Monitoring and recording requirements
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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.
Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Qualification and validation requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Qualification and validation requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Qualification and validation requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Qualification and validation requirements
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Conclusion
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
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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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Conclusion
A h t PIC St d d
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Approach to PIC Standard
Basic requirements for a GMP conform small volume parenteral production facility
Conclusion