Thursday, June 30, 2011

Sterile drug Injectable dosage form manufacturing facility inspection questionnaire

Questionnaire of Chemical Sterilization/Disinfection/ Sanitization in sterile drug manufacturing facility audit

162. What product (container/closure; manufacturing equipment) is sterilized by this method?
163. What is the sterilant, sterilant concentration and exposure time?
164. After sterilant exposure, does the item receive a final rinse and/or allowed to air dry?
165. Report the specifications for the final rinse water and/or air quality.
166. Briefly describe how the sterilized item is protected from recontamination before use.
167. Are there written procedures detailing all chemical sterilization processes?
168. Were these procedures followed with reference to their employment in the manufacture of the selected drug product?

Chemical Sterilization Validation
169. Describe the firm's validation of all chemical sterilization processes utilized, including completeness of documentation, the type of microbial challenges employed, and results.
170. Have any chemical sterilization processes changed since the last EI? Have these changes been evaluated for the need for revalidation?

Ethylene Oxide Gas Sterilization (EtO)
171. If EtO sterilization is performed by an outside firm, provide the name and address.
172. If EtO sterilization is performed in-house, give information about the sterilizer (autoclave) manufacturer.
173. What is the internal volume of the EtO sterilization?
174. What is the ratio of EtO to the carrier (%)(e.g., 12% EtO/88% Freon; 10% EtO/90% CO, etc.)?
175. Is a Certificate of Analysis received with the gas or analyzed by the user (specify which)?
176. Identify equipment/container/closure/other that is EtO sterilized as part of manufacture of selected drug product.
177. What is the sterilization cycle? (Compare Master Process Record/SOP specifications against processing records completed for the selected drug product.)
178. Is there preconditioning (specify external or in chamber, or both, at start of cycle)?
179. What are the firm's Master specifications and observed parameters for time, relative humidity and temperature?
180. Are biological indicators included in prehumidification cycle? Cycle Parameters
181. What are the Master specifications and observed parameters for the following:
a. Vacuum (mm Hg, in. H2O)
b. Air Venting other than by vacuum (prior to or during gas charging)
c. Temperature
d. Operating Pressure
e. Relative Humidity (%)
- at start of cycle
- during cycle
f. Preheating (heat exchanger ) or holding temperature of
gas when injected into chamber
g. Gas concentration in chamber (mg/Liter)
h. Use of a circulation fan
i. Exposure to sterilant (hrs.)
j. Use of Multiple Evacuation cycles (Number of cycles)
k. Come-Down or Evacuation Rate

182. How are each of the above parameters monitored? (specify when not monitored)
183. Specify method used to control addition of EtO to chamber (e.g.,chamber pressure, EtO concentration analysis, EtO weight measurement, other).
184. Specify method of moisture addition during cycle.
185. If more than one EtO sterilizer is used by the firm, or there are multiple EtO sterilization points within one EtO sterilization system, what is the system's capacity for maintaining established EtO levels when all chambers/sterilization points are operating
at the same time?
186. Explain length of supply line from bulk source, inside diameter, number of equipment serviced by supply line.
187. Are EtO concentration levels monitored in aeration and sterilization work areas? Specify levels.
give information about requested in for biological indicators used.
Residue Levels
188. Give information about procedures used to assure EtO residue removal (specify time, tamp., etc.)(e.g., hold in forced aeration area, hold in warehouse-ambient, etc.):
189. Give  firm's specifications and conformance for residue levels, if any.
190. What are the firm's specifications and observed levels of ethylene oxide (ppm), ethylene glycol (ppm) and ethylene chlorohydrin (ppm)?
191. Are the residue levels established according to any standard?
192. Obtain copy of dissipation curves (specify when not available).
193. If residue levels on the products are determined by a facility other than the manufacturer, give the name and address of the facility.
194. Have there been any changes in the EtO sterilization system since the last EI? Have these changes been evaluated for the need for re-validation?

Ethylene Oxide Validation
195. Does the firm have written procedures for validation that include:
(a) installation qualification of equipment
(b) operational qualification of equipment
(c) performance qualification with items to be sterilized
(d) description of circumstances requiring re-validation of the system and procedures to do so.

196. Does validation documentation include:
(1) empty chamber temperature distribution studies
(a) number of studies performed
(b) number of probes used and their location
(c) give firm's allowable variation and actual variation found
(2) empty chamber EtO concentration distribution studies
(a) number of studies performed
(b) number and location of probes utilized
(c) give firm's allowable variation and actual variation found
(3) empty chamber Relative Humidity Measurement studies
(a) number of studies performed
(b) number and location of probes utilized
(c) give firm's allowable variation and actual variation found
(4) Heat/EtO penetration studies performed:
(a) for each type of loading pattern to be utilized
(b) number of runs per pattern
(c) was the "cold spot" determined for each loading configuration
(5) What type of temperature/EtO/RH measurement systems were used?
(6) Is this equipment calibrated according to an established schedule, and traceable to an NIST standard where practible?
(7) Were measurement systems calibrated before and after each study?
(8) If biological indicators were used during validation run:
(a) type of indicator used
(b) source of indicator
(c) organism used
(1) concentration
(2) D value

Part 1 Inspection and facility audit questionnaire for sterile dosage form

Part 2 Sterile drug manufacturing facility audit questionnaire

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