Revised International Clean room Standard By Piyush Tripathi “Thought to Explore”

Revised International Clean room Standard By Piyush Tripathi

How do we classify Clean room? Clean room guidelines are having lot of loop holes as its still not so absolute to be acceptable as thumb rule. Speaking to industrial experts every individual has different opinion about the clean room standard, Classification and its construction. Few common questions that each will answer differently and as per the conditions prevail. Revised international clean room standards discussion is a constant updates that are punched on web and pharmacopeia as revisions. Major changes and standards discussions and clean room designed for one and later revised to non conformance. To overcome this new this we need to have an approach which is acceptable. Understand the process flow of material from one form the other.

Latest updates show a reasonable change in the classification of the clean room or aseptic condition building. As described in Pharmacopeia it states: A clean room, as defined in USP <797>, is a room in which the concentration of airborne particles is controlled to meet a specified airborne particulate cleanliness class. Microorganisms in the environment are monitored so that a microbial level for air, surface, and personnel gear are not exceeded for a specified cleanliness class.

Depending on the nature of the operation, work is performed in different clean room classes.  

Recommended Action Levels for Microbial Contamination

Process Area	Classification	Particle Count (maximum no. particles 0.5u or larger per m3 air	Air Sample (Cfu per cubic meter {1000 ltrs} of air per plate)	Fingertip Sample (CFU per pair of hands)	Surface Sample (Contact Plate) CFU/plate
Filling Zone	ISO Class 5	3,520	> 1	> 3	> 3
Buffer Zone	ISO Class 7	3,52,000	> 10	N/A	> 5
Entrance	ISO Class 8	35,20,000	> 100	N/A	> 100

Clean rooms and associated controlled environments – Part 1: Classification of air Cleanliness

USP<797> Pharmaceutical Compounding: Sterile Preparations US Pharmacopoeia.

CFU- Colony Forming Units

Filling Zone In ISO Class 5 Area.

Applications	USP<797> Requirement
Glove Cleaning	Routine Application of Sterile 70% IPA
Surface Cleaning	Wiping with residue free disinfecting agent such as Sterile 70% IPA
Dry Wiping & Spill Control	Low Shedding Wipes discard after one use
Isolator & Hood Cleaning	Cleaning and disinfecting surfaces frequently
Disinfecting	Compatible, effective non residual disinfectant solution

For Buffer Zone ISO Class 7 & Entrance ISO Class 8 Areas

Applications	USP<797> Requirement
Hand Washing	Hand cleansing procedure before gowning
Glove Cleaning	Disinfection of contaminated gloved hands
Decontamination of Cleaning supplies for filling Zone	Wipe outer surface with Sterile 70% IPA
Surface Cleaning	Low shedding wipes, discard after one use
Dry Wiping & Spill Control	Low Shedding wipes, discard after one use
Floor Mopping (Small Space)	Non shedding mop hands, preferably discard after one use
Floor Mopping (Large Space)	Non shedding mop hands, preferably discard after one use
Disinfecting	Wipe Supplies removed from cartons with a suitable disinfecting agent. Clean Floor with disinfectant Solution.

Section 211.42 (design and construction features) requires, in part, that aseptic processing operations be performed within specifically defined areas of adequate size.  There shall be separate or defined areas for the firm’s operations to prevent contamination or mix-ups.  Aseptic processing operations must also include, as appropriate, an air supply filtered through high efficiency particulate air (HEPA) filters under positive pressure, as well as systems for monitoring environmental condition, and maintaining any equipment used to control aseptic conditions.

Section 211.46 (ventilation, air filtration, air heating and cooling) states, in part, that equipment for adequate control over air pressure, microorganisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing or holding of a drug product.  This regulation also states that air filtration systems, including pre-filters and particulate matter air filters, shall be used. Appropriate filtration level to be maintained on air supplies to production areas.

Some known or assumed Air Classifications chart.

Clean Area Classifications	> 0.5 um particles/Ft3	> 0.5 um particles/m3	Micro biological Limit
100	100	3,500	< 1	<3 span="">
1,000	1000	35,000	< 2	< 7
10,000	10,000	3,50,000	< 5	< 18
1,00,000	1,00,000	35,00,000	< 25	< 88

Section 211.42 states that flow of components, drug products containers, closures, labelling, in-process materials, and drug products through the building or building shall be designed to prevent contamination. HEPA filtered air as appropriate classification and as per area required to be facilitated, as well as floors, walls and ceilings of smooth, non-particle shading surfaces that are easily cleanable are some additional requirements of this section.

Section 211.63 states that equipment shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. 

Section 211.65 states that equipment shall be constructed so that surfaces that contact the components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

Section 211.113 states that appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed.

Sections 211.22 states that, quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.

Section 211.113(b) addresses the procedures designed to prevent microbiological contamination, stating that written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed.

Section 211.25, Personnel Qualifications requires that each person engaged in manufacture, processing, packing or holding of a drug product shall have education, training and experience, or any combination thereof, to enable that person to perform the assigned functions. Adequate number of qualified personnel to perform and supervise the manufacture, processing, packing or holding of each drug product. Section 211.25 also requires that continuing training in CGMP shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.  The training shall be in the particular operations that the employee performs and in current good manufacturing practice, as they relate to the employee's functions.

Section 211.28, Personnel Responsibilities states, Personnel engaged in the manufacture, processing, packing or holding of a drug product shall wear clean clothing appropriate for the duties they perform. It also states that personnel shall practice good sanitization and health habits and specifies that protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination. It also states that any person shown at any time (either by medical examination or supervisory examination) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products.  All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products.

Restrictions on entry into limited access areas: Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited access areas.

Section 211.42 requires the establishment of a system for monitoring environmental conditions.

Guidelines and Classification of Class and Gradations

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 1,00,000	ISO 8	Grade D

Observations on the Clean Room Standards and revisions:

As summarized above for the process, production, packing and material areas clean room conditions are defined based on the process flow and its identifications. It’s not mandatory to have air locks to segregate or buffer the area, if area restrictions are there we can any time create a buffer area hold for man and material movement change the air present in the area and then move forward. Seems surprising but yes it is a possible solution for areas where space constraints and process limitation does not permit. This is entirely personal view. Why not?

Logic why do we create Air Lock? Answer to this is to obstruct person, media, product to enter another higher or lower classified area and ensure that the same is not contaminating or mixing up with or creating cross contamination. If we ensure that the sufficient amount of buffer is provided air lock and lot of space can be saved.

Modern method of aseptic processing are adapting to isolation principals that enables or isolates the processing area and the overall running cost of the process side can be minimized. Viz. processing area is isolated by making cubical which is entire process line is placed and outside area is normal Grade D. this helps to reduce the load of AHU of Grade A and due to lesser area overall running cost of the plant goes down. But selection of such principle is completely individual choice. Designing such area has to go through or counter lot of thumb rule followers who believe that the area should as prescribed in USP, IP, BP or any other pharmacopeia, it’s a matter of individual choices. People do think out of box but are forced to close the box as its one step that would require lot of explaining to do but there is always a first step.

Conclusion to revision in Clean Room Standards

By concentrating more on process requirements area can be designed to its absolute. Exploring possibilities with what we have is always the solution. Man has evolved and has made larger changes than what we are thinking of. Following law does not mean that one process can be done one way. SME organization, Job work organizations and individual local companies most of the time back off and does not explore the possibilities to upgrading their facilities as Law is often misinterpreted and misled. This blog is first “Thought to Explore”

“Thought to Explore”

First Step