Procedure for HVAC Qualification

1.0	PURPOSE This standard operating procedure provides guidance for qualification &requalification of area and HVAC system. It includes all classes of area.
2.0	SCOPE This procedure is applicable to all dosage form at Company name. The specifications described in this SOP are summarized from various guidelines for reference.
3.0	RESPONSIBILITY Executive QA/Head Engineering/Concern Deptt. Head
4.0	ACCOUNTABILITY  Head Quality Assurance
5.0	PROCEDURE
5.1 5.1.1 5.1.2 5.1.3      5.1.4 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6 5.2.7 5.3 5.3.1 5.3.2 5.4 5.4.1 5.5 5.5.1 5.5.2.1 5.5.2 5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.3 5.5.3.1 5.5.3.2 5.5.3.3 5.5.3.4 5.5.3.5 5.5.3.6 5.3.6.7 5.6 5.6.1 5.6.1.1 5.6.1.2 5.6.2 5.6.2.1 5.6.2.2 5.6.2.3 5.6.2.4 5.6.3 5.6.3.1 5.6.4 5.6.4.1 5.6.4.2 5.6.4.3 5.6.5 5.6.5.1 5.6.5.2 5.6.6 5.6.6.1 5.6.6.2 5.6.6.3 5.6.6.4 5.6.6.5 5.6.6.6 5.6.6.7 5.6.6.8 5.6.6.9 5.6.7 5.6.7.1 5.6.7.2 5.6.7.3 5.6.7.4 5.6.7.5 5.6.8 5.6.8.1 5.6.8.2 5.6.9	Following Parameters shall be reviewed during Area Qualification activity AREA Man and material movement Unidirectional Airflow Qualification (Wherever applicable) LAF (Clean air stations). Environment monitoring (Viable Particulate Matter) HVAC Temperature and Humidity Pressure differential Air velocity and Number of air changes Class of Air- Non-viable Particle count Airflow Direction/Pattern HEPA Filter integrity Parameters and Certificates, if provided by the supplier, the test may not be repeated. Data will be reviewed and considered. Men-material movement verification: Methodology: Using a prototype movement in the area, verification of men and material movement will be carried out with reference to the design specifications. Acceptance Criteria: Should be as per the designed specification. Unidirectional Airflow Qualification: Refer for LAF (Clean air stations). Environment monitoring (Viable Particulate Matter): For class A and B  For new area environment monitoring in each room shall be carried out for the not less than 7 consecutive days. The data is compiled for evaluation of area qualification. For class C For new area environment monitoring in each room shall be carried out for the not less than 5 consecutive days. The data is compiled for evaluation of area qualification. Monitoring is carried out by using settle plate method, Air sampling, and RODAC methods.  Monitoring shall be scheduled such that at least a test is performed in each shift. The number of TVC (total viable counting) shall depend upon the class and operation in that particular area. For class D For new area environment monitoring in each room shall be carried out for the not less than 3 consecutive days. The data is compiled for evaluation of area qualification. Monitoring is carried out by using settle plate method, Air sampling, and RODAC methods. The preferred location for the exposure of the settle plate and Air sampling is near to return duct, low level exhaust and drain in the particular area and for RODAC, it shall be near drains, door handles, floor, wall & outer surfaces of equipments. The selection will be depending on the approach to the location. Sampling methods used during operation should not interfere with zone protection. For existing areas, data for environmental monitoring from last qualification shall be reviewed & trend shall be prepared. Recommended limits for microbiological monitoring, as per Annexure 1 - EU guidelines for clean areas are given in Table-1. These limits are considered as action limits. Notes: (a) These are average values. (b) Individual settle plates may be exposed for less than 4 hrs. Based on the trends, appropriate alert and action limits should be set for particulate and microbiological monitoring. If these limits are exceeded, respective operating procedures should prescribe action plan. Temperature and humidity mapping in area : Area with Forced Circulation of Air: Methodology: Temperature and Humidity mapping will be done minimum at one location i.e. center of the room for not less then 3 consecutive days for new facility & 1 day for modified facility using calibrated Hygrometer, portable data logger or any suitable instruments. Acceptance criteria: Temperature should not exceed 27°C and Relative Humidity not to exceed 55 % unless specified. Area at ambient: Methodology: Temperature and Humidity mapping will be done using calibrated Hygrometer, portable data logger or any suitable instruments. The monitoring instrument is kept at working height i.e. between 4-5 feet. Monitoring is carried out at minimum five locations i.e. four corners & center of the room. The locations for monitoring are followed as per the schematic plan depicted below.The recording will be done for not less than 3 consecutive days. Note: All the data will be recorded in rest condition (unmanned). Locations for Temperature & RH monitoring For periodic monitoring available data on the record is reviewed. Acceptance criteria: Temperature shall not exceed 40°C. Pressure Differential:                                              Methodology: Pressure differential values of the rooms under consideration and also of LAF’s (Clean air stations) are to be recorded in the appropriate format. The pressure differential values were valid only when all the doors of area are closed. Acceptance criteria: Acceptance criteria Minimum requirement for pressure gradient as per Schedule M U.S.FDA Draft In-house Criteria Pascal mm of Hg Pascal mm of Hg Pascal mm of Hg Pressure differential between adjacent room of different grade 15  1.5 12.5 - NLT 16 1.6 Pressure differential adjacent room of same grade - - 5 - NLT 6 0.6 In house criteria are defined based on the least count of measuring device. Air Velocity and Number of Air Changes –  Air Velocity Measurements: Air velocity measurements are to be done using an Anemometer. Minimum of 5 measurements are to be made for each filter i.e. 4 in the corners and 1 in the center of the filter face. All the velocity measurements are to be made at a distance of not more than 6² from the filter face. Average of 5 readings willbe considered for number of air changes. Record the velocity measurement data in the appropriate format. Air Changes Delivered: The number of air changes delivered per hour by the HVACsystem is to be calculated for all the rooms classified as Class A, B, C and D. The calculations are to be done utilizing the air velocity measurements recorded in the format for velocity measurement. The numbers of air changes in a particular area shall be calculated as per illustration given – Where S1, S2, S3, S4 were supply air ducts of dimensions A and B respectively. S1 the Velocity readings are 1,2,…5 S2 the Velocity readings are 1,2,…5 S3 the Velocity readings are 1,2,…5 S4 the Velocity readings are 1,2,…5 An average velocity will be calculated as per the equation ΣV/ nWhere V is velocity in (m/sec) and n is number of readings ΣS = Summation of surface area of inlet air filter like, For S1 Area = AXB (meter2 ) {plus area of all filters} C= Volume of Room= length X width X height of room (meter3 ) 3600 is the conversion factor for per second to per hour Record the observations of the calculations of each room in the appropriate format. Number of air changes per hour = åV / n *åS *3600                                                                  C Acceptance Criteria: The number of air changes should not be less than 20. Class of Area-Non Viable Particle Count – General classification: As per different references, the class of area is defined as Table no. 2: For classification of area ISO Grade SI Customary 5 A M 3.5 100 6 B M 3.5 100 7 C M 5.5 10,000 8 D M 6.5 1,00,000  Requirement of “At Rest” and “In Operation” are defined as per EU guidelines. Following are the non-viable air borne particulate matter requirement for different grades. Table no. 3 : Maximum number of particulate matter as per Class calculation (Per Cubic Meter) At rest (a) In operation (b) Number of particles (a) ISO Grade 0.5 µ 5 µ 0.5 µ 5 µ 5 A 3500 1 3500 1 6 B 3500 1 3,50,000 2000 7 C 3,50,000 2000 35,00,000 20000 8 D 35,00,000 20000 Not Defined Not Defined Alternatively, Number of particles (Per Cubic Feet ) At rest (a) In operation (b) Number of particles (a) ISO Grade 0.5 µ 5 µ 0.5 µ 5 µ 5 A 100 0 100 0 6 B 100 0 10,000 57 7 C 10.000 57 1,00,000 570 8 D 1,00,000 570 Not Defined Not Defined Notes: (a) At rest: the condition is unmanned and no activity is carried out in the area. The area is left aside for 20 minutes before starting the measurement. For routine testing the total sample volume should not be less than 1m3 for grade A, B and C areas. (b) The particulate conditions for grade A “in operation” may not always be possible to demonstrate on formity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. It is acceptable however, data shall be recorded. (c) These areas are expected to be completely free from particles of size greater than or equal to 5μm. As it is impossible to demonstrate the absence of particle with any statistical significance the limits are set to 1 particle / m3 . During the clean room qualification it should be shown that the areas could be maintained within the defined limits. (d) Maximum permitted number of particles in the “at rest “and “in operation “conditions. Examples of operations in different grades of areas Grade Examples of operations Grade for A Aseptic preparation and filling Grade C for  Preparations of solutions to be filtered Grade D  for Handling of components after washing, RM dispensing, RM sampling and non-sterile dosage General principles for the Particulate matter counting: The cleanliness class verification of the rooms as well as the area below the HEPA filters (LAF’s / Clean air stations) are to be done using an air particulate matter counting device, at rest phase. The numbers of locations for performing the counts in the area of non-unidirectional airflows (In the rooms) are to be calculated using the following equation Number of Locations = NL  =√A Where Nl = No of sampling location A = Area of the clean room/ clean zone in m2 . This is the basis for consideration for the number of locations for critical areas like, filling area in which aseptic manufacturing is carried out. Based on area, minimum location for particulate matter counting in Class C is 10. for class D and other areas minimum locations should be not less than 5. For LAF’s (Clean air stations) refer SOP  The priority of the locations should be near to return duct and in vicinity of equipment. The pressure differential across the filter is to be checked and recorded during the particulate matter counting.  Data on particulate count is monitored at room temperature. Mark the locations at which the particulate matter counts are performed in the copy of the layout attached.  Record the observations of the counts at each location in the appropriate format. Statistical evaluation of the measurement data of the counts obtained for any one of the particle sizes (data of 0.5 µpreferred) shall be performed. Always Calibrated Particle counter shall be used & its calibration certificate should be available. Air Flow Direction / Pattern Verification – Methodology: The airflow pattern / direction verification is to be done by generating avisible smoke using Titanium tetra chloride (TiCl4) liquid. A glass rod or a suitable device is to be immersed in the liquid and held in the room or under the LAF. For LAF (Clean air stations): The pattern verification is to be done 6” away from the filter face towards the point where the actual activities are performed. For Area: The doors opening and closing, return duct, point exhaust will be considered for the airflow pattern verification. Flow of smoke is to be recorded diagrammatically in the area layout. Additionally photographs or video graphs may also be taken & kept in record for area & LAF. Acceptance Criteria: Should comply as per the designed specification. HEPA Filter Integrity Testing – Methodology: HEPA filter integrity testing is to be done for all the filters installed inside the plenums of AHU’s, at the terminus of air supply ducts and in the LAF workstations.An aerosol spray created by passing compressed air through DOP (Di-Octyl Phthalate) or PAO (Poly alpha olefins) liquid is to be introduced above the HEPA filters (upstream) and the downstream of the filter face including the periphery is scanned with a probe of an aerosol photometer (scanning exercise is to be carried out for all the filters). Attach the reports of integrity testing in appropriate format. Acceptance Criteria: The leakage should not be more than 0.03%. High efficiency particulate air filter with minimum 0.3 μ particle retaining efficiency of 99.97%.  Requalification: Area & HVAC shall be requalified for various parameters at the frequency as defined as in Schedule M – Drugs & Cosmetics Act, India, ISO-14644-2- Specification for testing & monitoring to prove continued compliance with ISO-14644-1 and PDA Journal of Pharmaceutical Science and Technology, 2003 Volume-57, Supplement-2. Requalification schedule may vary by one month, but more then one month deviation from frequency shall be justified.
6.0	REFERENCES     NIL

7.0

ANNEXURES

Annexure No.	Title of Annexure	Format No.
Nil

8.0	ABBREVIATIONS

Abbreviations					Full Forms
SOP					Standard Operating Procedure
QA					Quality Assurance
HEPA					High Efficiency purified air
AHU					Air Handling unit
9.0	DISTRIBUTION
Master Copy						Head Quality Assurance Department
Controlled office Copy No. 1						Head Quality Assurance Deptt.
10.0		REVISION HISTORY
S.No.		Revision No.	Effective Date	Reason for Revision			Details of Change	Authorized By (sign & Date)