Aseptic, Terminal Sterilized Process, Area Grading & Cleaning Procedure in Pharma

Standard Operating Procedure of Aseptic, Terminal Sterilized Process, Area Grading & Cleaning Procedure in Pharma is describe in this post.

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1. PURPOSE

1.1 To describe the method for aseptic processing, terminal sterilization of Injectable, area classification and its cleaning procedure

2. SCOPE

2.1 The procedure is applicable to sterile section.

3. RESPONSIBILITY

3.1 Operator injectable section is responsible to follow the procedure. 

3.2 Production Pharmacist is responsible to 

3.3 Production Manager is responsible to implement the procedure.

3.4 Q. A. Officer is responsible to verify the procedure.

4. MATERIAL & EQUIPMENT

4.1 Isopropyl Alcohol

4.2 Dettol

4.3 Proceine 40

4.4 Q’BAC

4.5 Lint free duster

4.6 Mop

5. PROCEDURE

5.1 DEFINITIONS:

5.1.1 CLEAN ROOM

a. A room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the room and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as necessary.

5.1.2 CLEAN ZONE

a. Dedicated space in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the zone, and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as necessary.

b. The zone may be open or enclosed and may or may not be located within a clean room.

5.1.3 AS BUILT

a. Condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present

5.1.4 AT REST

a. Condition where the installation is complete with equipment installed and operation in a manner agree upon by the customer and supplier, but with no personnel present

5.1.5 OPERATIONAL

a. Condition where the installation is functioning in the specified manner, with the specified number of personnel and working in the manner agreed upon

5.1.6 ACTION LEVEL

a. Level set by the user in the context of controlled environments, which, when exceeded, requires immediate intervention, including the investigation of cause, and corrective action.

b. Established microbial or particulate monitoring results requiring immediate follow-up and corrective action.

5.1.7 ALERT LEVEL

a. Level set by the user in the context of controlled environments, giving early warning of a drift from normal conditions, which, when exceeded, should result in increased attention to the process

5.1.8 AIRLOCK

a. Room with interlocked doors designed to maintain pressure control between adjacent rooms of different cleanliness class.

5.1.9 ASEPTIC PROCESSING

a. Handling of sterile product, containers and/or devices in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to maintain sterility

5.1.10 ASEPTIC PROCESSING AREA

a. Facilities for aseptic processing, consisting of several zones

5.1.11 BIO-BURDEN

a. population of viable microorganisms on or in product and/or sterile barrier system

5.1.12 BIO-DECONTAMINATION

a. Removal of microbiological contamination or its reduction to an acceptable level

5.1.13 CLEANING

a. Removal of contamination from an item to the extent necessary for further processing or for intended use.

5.1.14 CORRECTION

a. Action to eliminate a detected nonconformity.

5.1.15 CORRECTIVE ACTION

a. Action to eliminate the cause of a detected nonconformity or other undesirable situation.

5.1.16 CRITICAL PROCESSING ZONE

a. Location within the aseptic processing area in which product and critical surfaces are exposed to the environment.

5.1.17 DE PYROGENATATION

a. Validated process designed to remove or deactivate endotoxins.

5.1.18 ENDOTOXIN

a. Lipopolysaccharide component of the cell wall of Gram-negative bacteria which is heat stable and elicits a variety of inflammatory responses in animals and humans.

5.1.19 PREVENTIVE ACTION

a. action to eliminate the cause of a potential nonconformity or other undesirable potential situation

5.1.20 STERILE

a. Free from viable microorganisms.

5.1.21 STERILIZATION

a. validated process used to render a product free from viable microorganisms

5.1.22 TERMINAL STERILIZATION

a. Process whereby product is sterilized within its sterile barrier system.

5.2 Classification Number: 2.08 

                                            C_n = 10^N x [0.1/D]

C_n represents the maximum permitted concentration (in particle/m3 of air) of airborne particles that are equal to or larger than the considered particle size; Cn is rounded to the nearest whole number

N is the ISO classification number, which shall not exceed the value of 9. Intermediate ISO classification numbers may be specified; with 0.1 the smallest permitted increment of N

D is the considered particle size in μm

0.1    is a constant with a dimension of μm

5.3 Categories of sterile products

a Those that can be sterilized in final container (terminally sterilized)

b Those that cannot be terminally sterilized and must be aseptically prepared 

5.4     Aseptic Process

A Simple process flow for aseptically processed products.

5.5 Terminally Sterilization Process

a. A simple Process Flow for Terminally Sterilized Products

5.6 Clean Room Grading and Classification

5.6.1 Four grades of clean areas:

a. Grade D (equivalent to Class 100,000, ISO 8):

Clean area for carrying out less critical stages in manufacture of aseptically

prepared products e.g., handling of components after washing.

b. Grade C (equivalent to Class 10,000, ISO 7):

Clean area for carrying out less critical stages in manufacture of aseptically

prepared products e.g. preparation of solutions to be filtered.

c. Grade B (equivalent to Class 100, ISO 5):

Background environment for Grade A zone, e.g.,cleanroom in which laminar

flow workstation is housed

d. Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5

(ISO 14644-1):

• Local zone for high risk operations e.g., product filling, stopper bowls,

open vials, handling sterile materials, aseptic connections, transfer of partially

stoppered containers to be lyophilized.

• Conditions usually provided by laminar air flow workstation.

5.6.2 Each grade of clean room has specifications for viable and non-viable

particles.

5.6.3 Non-viable particles are defined by the air classification

5.6.4 DIFFERENTIAL PRESSURES

a. Positive pressure differential of 10-15 Pascal should be maintained between

adjacent rooms of different classification (with door closed). A differential air

pressure of 0.04 to 0.06 inches water gage is recommended between spaces.

b. Most critical area should have the highest pressure

c. Pressures should be continuously monitored and frequently recorded.

d. Any deviations should be investigated and effect on environmental quality

determined

5.6.4 Ambient temperature and humidity should not be uncomfortably high (could

cause operators to generate particles).

5.6.5 AIRFLOW VELOCITY

a. Laminar airflow workstation air speed of approx. 0.45m/s ± 20% at working

position (guidance value)

5.6.6 CLOTHING OF APPROPRIATE QUALITY: a. Grade D • hair, beard, moustache covered • protective clothing and shoes b. Grade C • hair, beard, moustache covered • single or 2-piece suit (covering wrists, high neck), shoes/overshoes • no fibres/particles to be shed c. Grade A and B • headgear, beard and moustache covered, masks, glovesnot shedding fibres,

and retain particles shed by operators • Outdoor clothing not in change rooms leading to Grade B and C rooms • Change at every working session, or once a day (if supportive data) • Change gloves and masks at every working session • Frequent disinfection of gloves during operations • Washing of garments – separate laundry facility • No damage, and according to validated procedures (washing and sterilization) • Regular microbiological monitoring of operators

5.7 Comparison of classifications

WHO GMP	US 209E	US Customary	ISO/TC (209) ISO 14644	EEC GMP
Grade A	M 3.5	Class 100	ISO 5	Grade A
Grade B	M 3.5	Class 100	ISO 5	Grade B
Grade C	M 5.5	Class 10,000	ISO 7	Grade C
Grade D	M 6.5	Class 100,000	ISO 8	Grade D

5.8 CLEANING PROCEDURE OF STERILE AREA

5.8.1 Cleaning Procedure of Grade A Area

a. At the end of the day’s operation, promptly remove all unwanted material

from the sterile area. b. Machine parts that are directly contacts with products and can be autoclaved,

are washed with water for injection and are double raped with parachute bags and

then autoclave it. c. Laminar Air Flow Hood Curtain are wiped with lint free wipe and moped with

70 % IPA. Moping is done from upper side to lower side with wipe folded and

other side of wipe is used. Wiping is unidirectional. d. Machine is wiped from upper side to lower side and is unidirectional. e. Machine bench is wiped from machine to outer side and unidirectional with

lint free wipe. f. 70 % IPA solution spray should be done interval. g. After one week, disinfectant is changed with Proceine 40. Rotation of

disinfectant is necessary. h. Proceine 40 • Proceine 40 is concentrated germicide solution of alkyl-amino-alkyl-glycines. • Add contents of sachet to water for injection. • Mix in order to homogenize. • Apply by hand spray, disposable wiper, and mop or by immersion in order

to wet down all surfaces. • Allow contact time of 5 minutes. • There is generally no need to rinse after application. i. Q’BAC • Active ingredient in Q’ BAC is Triclosan 0.2 % w/w. • For general cleaning, dilute up to 1:1200 parts of hand water (5ml per

5 liters, 1 tsp per 5 ltr). • Mop or wipe the surface with it. • After use rinse and dry hands. For prolonged use it is advisable to wear

rubber gloves. j. Dettol • Active ingredient in Dettol is Chlorxylenol. • Add 200 ml in 5 Liters of Water for injection. • Mop or wipe the surface with it 5.8.2 Cleaning Procedure of Grade B Area a. At the end of the day’s operation, promptly remove all unwanted material

from the sterile area. b. Cleans the ducts and roof with lint free mop. c. Mop the walls and glass window and doors in such a way that moping should

be unidirectional and from upper side to lower side. d. Then mop the floor in such a way that mopping should be unidirectional and

from machine to door side. e. Use disinfectant as mention in Grade A area. 5.8.3 Cleaning Procedure of Grade C and D. a. Mop these areas with Dettol and spray with IPA 70 %. b. Clean the roof first and ducts. c. Mop the walls in such a way from upper side to lower side. d. Moping should be unidirectional and to door side.

5.9 PRECAUTIONS

5.9.1     Follow entry and exit procedure in critical areas. 5.9.2     Follow gowning and de-gowning procedure. 5.9.3     Moping and cleaning should unidirectional. 5.9.4     Moping should be from upper side to lower side. 5.9.5     Moping should be from machine side to door side.

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