Free Essay On Biex Pharmaceuticals

Aseptic Pharmaceutical Production Facility

Abbreviations
cGMP current Good Manufacturing Practices

HEPA High Efficiency Particular Air

QA Quality Assurance
QC Quality Control
PW Purified Water
USP United States Pharmacopeia
sWFI Sterilized Water for Injection

Introduction

BieX Pharmaceuticals is producing a new process of dissolution of a dry Active Pharmaceutical Ingredient (API) in sterilized Water for Injection (sWFI). The resulting solution will be filled in the similar volume containers and then terminally sterilized.
The manufacturing will comply with all cGMP guidelines. The sterilization procedure will comply with relevant specifications to ensure that no pyrogens or bacterial endotoxins are present. The final dosage form should be free of particulates.

General

The facility will be housed in a separate facility from our main offices. Only authorized people consisting of production people, quality assurance, and quality control will have access to the facility. The new facility is renovated from an old storage facility. Key-carded doors will be installed and only personnel with access will be allowed to enter the facility. Sticky mats are placed at the door to capture any dirt from shoes. The facility consists of a storage room where raw material is stored, an anti-room where personnel can change and the production room in which a cleanroom facility is present. The dimensions of the class 100 (ISO 5) cleanroom are a square 25 m x 25 m x 10 m.
The facilities inside are modular with only sinks, electrical outlets being stationary. This will ensure that equipment that is commissioned or decommissioned can enter or exit the room with relative ease. The sinks discharge PW for general washing. There are no unsealed openings. Drains are connected to the main facilities sewage system. Floor drains are fitted with traps to prevent any backflow. Sinks and drains should be prohibited in grade A/B areas. Drains in grade C areas should be sanitizable. Several electrical outlets giving both 140 and 250 W output for any instruments or machinery that need electricity.
The walls are and ceiling are smooth and curved so there are no corners within the room minimizing any projecting ledges where dust can collect. There are no shelves or cupboards. Any small equipment is stored on metal trays that can be autoclaved. Any particulate matter from paper or clothing are not permitted in the room. Quality control have the ability to view from outside through two windows that are attached to the facility. Additionally, there is a cabinet open to the outside where samples and batch records can be passed. Doors entering to the facility are solid one piece tempered glass and easy to clean.

Key Challenges

There are many key challenges when designing this from the company level to the personnel level. The key challenges would be developing a facility that can be used for producing multiple drug compounds. It is a challenge for the process of materials as there will only be in and one out. Another challenge to keep unwanted people out of the facility. Finally, the people that are within the facility they have to be safe and comfortable.

Diagram of Cleanroom

Lighting & Electrical
Outside and Inside Cleanroom facility
Phillips Hygeia TBH318 will be installed both inside and outside. It is functional as it has two fluorescent lamps with a parabolic mirror and a clear plastic cover. It is also easy to clean as it does not have protruding rims and is totally flat. Lighting should cover the whole facility so no surface is left in the dark.

All appropriate electrical comes from the ceiling and is tested to avoid shock or surges.

Ventilation
Between the storage facility and the clean room there are a set of airlock doors. One door needs to be closed in order to open the other one. An audible and a visual red light alarm will be sounded if both doors are open at the same time. This will also indicate a QA deviation.
Positive airflow will go from the cleanroom to the lower grade outer surrounding rooms when the clean room is operational. Lower grade HEPA (High Efficiency Particular Air) filters will be used in the outer facility. There should not be a pressure differential of 10-25 Pascals (pressures are recorded during operation). Outside the clean room there will be turbulent airflow patterns. Environmental monitoring (QA) should ensure that these flows do not present any kind of risk by distribution of particulate.

Within the Clean Room Facility

Within the cleanroom we will have laminar flow. To reduce any particulates high particulate HEPA (High Efficiency Particular Air) filters will be used. This system will use a constant downward stream towards the floor and go through floor panels for recirculation. The HEPA filters are tested for integrity three days prior to operation of the clean room facility. Environmental monitoring techniques like contact plates, swabbing and air sampling will be conducted by QA to ensure that the air quality is sufficient and not moving particulates within the facility.
In regards to the airflow, people working within the facility should restrict movement as much as possible to avoid too much turbulent air flow.

Raw Materials & Water

Dry powder raw materials are delivered from the main site in 5 L plastic reusable containers. All raw materials are stored within the facility in locked metal cages inside a storage unit. Cages can be cleaned from the outside and wheeled into the cleanroom facility. Sterile WFI (sWFI) is also delivered within the same way from a different site and stored in a different metal cage. Both the water and raw materials are wiped prior to entering the cleanroom to remove any particulate during transport.

There are two different types of water systems on site purified water (PW), and sterile water for injection (sWFI).

Firstly PW is used for washing, steam cleaning and for filling any waterbaths within the clean room facility. This water is prepared from the cities potable water source. This water comes from the main facility and is filtered through (reverse osmosis, ion exchange and UV system) outside the facility clean room before use within the clean room. This water should fit the parameters of PW from USP (Table 1) before being used within the cleanroom facility. It is protected from contamination and goes through fitted pipes to the facility. PW is tested by QA on a regular basis to ensure quality for microbial contamination.
The second water present within the facility is the sWFI which will be used for flushing product contact surfaces after cleaning with PW and will be present in the final solution with the API. The WFI is prepared by distillation and housed in its own private facility.
Lastly sWFI is produced from two viable sources and shipped as a raw material. This will save money for developing a facility for sterilizing our current WFI water, reduce costs when the facility is not in use, and it will allow easier tech transfer of the production in the future. Additionally, using an external supplier will allow good trackability of lot number for the final product.
The water should be able to dissolve the API. As the API we are using has a higher dissolution rate and is slightly hydrophobic the sWFI needs to be heated prior to adding the material. This is achieved through water baths attached to the reactors where dissolution occurs.

Temperature & Humidity

Outside the cleanroom
Ambient temperature and ambient humidity are sufficient for the outside of the cleanroom facility.
Within the cleanroom
As full length cleanroom garments worn and people are present in the cleanroom for lengthy periods of time the ambient temperature within the cleanroom should be low around 20oC.
As we will be working with dry API. Within the facility all precautions should be taken to make sure that the humidity is low when the dry raw materials are opened. This will prevent any caking of the materials and increase the amount of dissolution time.

Cleaning of Equipment and Facility

Outside Cleanroom
Equipment is cleaned outside the facility before being placed in the cleanroom. The outside facility storage room is cleaned to appropriate conditions to eliminate any bioburden or particulate matter from coming into via personnel into the cleanroom.

Within Cleanroom

All stationary parts: walls, lighting, sinks and electrical cords are cleaned prior moving equipment into the cleanroom. The equipment is cleaned by validated methods to eliminate bioburden and particulates. Here we use a steam in place. It is the best sterilization of equipment by heat. This will be for all process equipment including the piping between the units. Before use a final rinse is done with sWFI. A check can be done for each before and after to determine the validity of the clean.

Waste

The only waste generated within the facility will be from sWFI packages. A waste handling container will be present on the metal cage to capture the sWFI packages. The reusable plastic 5L containers for the dry API will closed and weighed by QA as a double check to ensure that all the API was added to the final formulation. The API are a hazardous material any waste should be recorded.

Final Vial Fill and Distribution

The batches should be filled and processed and placed into vials. A closed cart will take the vials for distribution
Other
All appropriate regulations for fire, hazardous materials and facility shutdown will be installed within both units.

References

DIN 58950 (2003) Sterilization – Steam sterilizers for pharmaceutical products
Part 7: Requirements on services and installation
DIN EN 13824 (2005) Sterilization of medical devices –
Aseptic processing of liquid medical devices – Requirements ISPE Water Steam Guide
DIN EN 285 (2006) Sterilization – Steam Sterilizers – Large Sterilizer
HTM 2010 Sterilization – Steam Sterilizers – Large Sterilizers USP 29-NF24 Supplement No.1 (2006)
USP 24-28
Guidance for Industry Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice September 2004,. Accessed April 8, 2015
http://www.fda.gov/downloads/Drugs//Guidances/ucm070342.pdf