Approach to PIC Standard

Basic requirements for a GMP conform small volume parenteral production facility

Page 1

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Content:

Introduction
Clean room classification requirements Process equipment requirements

HVAC + clean room requirements

Process utilities requirements Monitoring and recording requirements

Qualification / validation requirements

Conclusion
Page 2

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Introduction

Page 3

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Introduction

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)

The primary container:

Vials Ampoules Syringes Cartridges

Page 4

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Introduction

The process (example syringes):

Class C Class B
Caps

Class D

Class E

Sterilizing tunnel

Prefilter

Washing machine

Compounding vessel

Sterile filter

Mobile vessel LAF class A

Primary containers

LAF class A
Liquid and solid active ingredients and excipients

Stoppers

Secondary packaging

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
Page 5

RISK

Inspection

Filling

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Clean room classification requirements

Page 6

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Clean room classification requirements

What characterises a pharmaceutical clean room:

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
Page 7

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 Main activity A B C
Background of filling in case the product can be terminally sterilized. Sampling, weighing and compounding of products which can be sterile filtered before filling

D
Washing of used equipment. Background for washing and sterilizing of primary packaging material. Background for filling in case of isolator technology

Background of Filling of small class A volume parenteral products Complete production process in case of aseptic process with no possibility to sterilize the product

EU-GUIDE ISO 14644-1 Particles/m 0.5 m 5 m CFU/m

3 3

A 5 Rest* <3.500 5 Oper. <3.500 5 Rest*

B 7 Oper. <2.000 <10 7 Rest* <2.000 --

C 8 Oper. <20.000 <100 8 Rest*

Oper. --

<3.500 <350.000 <350.000 <3.500.000

<3.500.000 <20.000 --

<1
--

<1
<1

<1
--

-< 200

* after clean-up phase of 15-20 min

Page 8

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 Activity O* Manufacturing of open, non-sterile products E Manufacturing with closed product (inspection, warehouse, secondary packaging etc.) Rest** ---Operation ---F Non-manufacturing area: (Labs, QC, administration, workshops, engineering, canteen) Rest** Operation in principle no requirements, non-GMP in principle no requirements, non-GMP in principle no requirements, non-GMP

Particles/ m3 0.5 m 5 m CFU/ m3 *

Rest** <3.500.000 <20.000 --

Operation ----

In accordance with hygiene zone D, without being legally binding, however; Pharmaplan recommendation internal customer standard user-defined, process-specific adaptations are possible. ** after clean-up phase of 15-20 min

Page 9

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Clean room classification requirements

Classification of activities / rooms:

Activity/room None aseptic process (sterilization within final container) D + LF D + LF D + LF D + LF D + LF D D + LF A in D A in C D E E E F F F (up to class D) F Aseptic process (sterile filtration before filling) C + LF C + LF C + LF C* or A in B D + LF D D + LF A in D A in B A in B D + LF E E F F F (up to class D) F Aseptic process (from sampling up to primary packaging) A in B A in B A in B D + LF D D + LF A in D A in B A in B D + LF E E F F F (up to class D) F

Weighing/sampling Raw material handling (e.g. milling, sieving, mixing) Compounding Sterile filtration Washing + primary packaging of stoppers Pre-washing of equipment in direct contact with the product Last rinsing (WFI) of equipment in direct contact with the product Sterilization + depyrogenation of primary packaging material, including transport Filling + stopper placement of open containers Transfer to freeze dryer Crimping Product sterilization Inspection of closed primary containers Secondary packaging Quality conttrol Workshop Product offices Canteen for eating and drinking * if closed system

Page 10

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Process equipment requirements

Page 11

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Process equipment requirements

General issues to consider for the design of process equipment:

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 other equipment, 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

Page 12

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Process equipment requirements

Polished stainless steel; < 5m

Example: Material requiremetns

This is required for product contacting parts such as: - compounding vessel - filling machine - WFI; PW and clean steam system

Microorganism

Microorganism

This is sufficient for secondary equipment such as: - inspection machines - packaging machines - Non product contacting surfaces (e. g. filling machine, claddings etc.)
Page 13

Polished stainless steel; Ra <0,8m

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

HVAC and clean room requirements

Page 14

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility HVAC and clean room requirements

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

Page 15

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility HVAC and clean room requirements

Working principles of HVAC units:

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 units Variable 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)
Page 16

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility HVAC and clean room requirements

Airflow principles in the clean room:

turbulent mixing system (class B, C and D)

laminar flow system (vertical flow) (class A)

laminar flow system (horizontal flow) (class A)

Page 17

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 A Air changes/h Prefilter Final filtering Overpressure [Pa] Floor exhaust Temperature [C] rel. Humidity
0,45m/s 20%* F7 + F9 HEPA/H14 Unidirectional airflow X 19-21 < 55%

Standard Pharmaplan C
20 F7 + F9 HEPA/H13 +15** 19-26 < 65%

B
20-60 F7 + F9 HEPA/H13 +15** (X) 19-21 < 55%

D
10-15 F7 + F9 HEPA/H13*** +15** 19 - 26 < 65%

O
5-15 F7 + F9

E
5-10 F7

F
3-10 F7

+15** 19 - 26 < 65%

0 19 - 30 < 65%

0 19 - 30 < 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

Page 18

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:

Page 19

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Process utilities requirements

Page 20

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Process utilities requirements

Process utilities:
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 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
Page 21

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

Page 22

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Process utilities requirements

Generation of pharmaceutical water:

European requirements (EP / EMEA) Purified Water Production by... Ion exchange Distillation WFI Distillation HPW e.g. Doublereverse- osmosis in connection with other suitable techniques such as Ultra-filtration and Electro Deionisation Drinking water US-FDA requirements (USP) Purified Water Appropriate process, e.g. deionisation, Ion-exchanger, distillation, reverse osmosis or other suitable processes WFI Distillation or Other suitable process*

Reverse osmosis Other suitable methods

Produced from... Monitoring

Drinking water

Drinking water Purified water Conductivity TOC, Endotoxine, Microbiological

Drinking water

Drinking water Purified water Conductivity TOC Endotoxine, Microbiological

Conductivity TOC Microbiological Nitrat, Heavy metals

Conductivity TOC Endotoxine, Microbiological

Conductivity TOC Microbiological

* 1st supplement to USP 27: WFI is water purified by distillation or a purification process that is
equivalent or superior to distillation in the removal of chemicals and micro organism
Page 23

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Monitoring and recording requirements

Page 24

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Monitoring and recording requirements

GMP requirements for monitoring and recording...

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 normally done within the risk analysis process (GMP risk analysis)

Page 25

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 to a 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

Page 26

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Monitoring and recording requirements

Page 27

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Qualification and validation requirements

Page 28

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Qualification and validation requirements

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 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
Page 29

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Qualification and validation requirements

Basis RA

Detail RA

Engineering

Construction Transport / Installation

Commissioning

Process start up / test runs

ProcessOptimisation

Routine Production

URS

FDS/DQ

FAT

IQ

SAT/OQ

PQ

PV / CV Re-Qual.

Change Control Procedure

Page 30

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 Process Validation, 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 of GMP. 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 in accordance 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.

Page 31

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Qualification and validation requirements

Example: Validation Master Plan

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

Front Page Introduction (Purpose, Target) Validation Philosophy Organisation Project Description Timetable and Capacity Plan Risk Analysis Qualification Validation Change Control Personnel Training Annex

provide up to date information about the actual state of affairs relating to validation demonstrate the firms commitment to carry out adequate validation

Page 32

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: Annex 11: Annex 15:

Chapters 5 + 6 Computerised Systems 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 Requirements for Finished Pharmaceuticals, Proposed Rule; May 1996 Guides for Inspection

PIC

PIC/S-Document PI 006-1 Validation Master Plan, Installation and Operational Qualification, Non-sterile Process Validation, Cleaning Validation
PIC/S-Document PI 007-1 Validation of Aseptic Processes

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

Page 33

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility

Conclusion

Page 34

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Conclusion

Some points to consider... The technical complexity of a project is driven mainly by the product, the process 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 change control 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 measures before official inspections

Page 35

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Conclusion

Some of the most relevant guidelines... US-FDA Guidance 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 active pharmaceutical ingredients (Annex 1) www.emea.eu PIC Guide to good manufacturing practice of medicinal products (July 2004) www.picscheme.org ISPE Baseline Guide: Pharmaceutical engineering guides for new and renovated facilities; Volume 3 Sterile manufacturing facilities www.ispe.org

Page 36

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Conclusion

Page 37

Approach to PIC Standard Basic requirements for a GMP conform small volume parenteral production facility Conclusion

Page 38