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Monday, June 27, 2011

Sterile drug manufacturing facility audit questionnaire Part 2

Useful questions for conducting sterile drug manufacturing facility audit. Part 2

The following reference questions are provided for evaluation of specific drug products, manufacturing systems, and quality control procedures in sterile dosage form manufacturing.

1. Does the firm have adequate written procedures describing the receipt, handling, that are represented to be sterile and/or pyrogen free? (per 21 CFR 211.80 - 211.94; 211.184)
2. Have these procedures been followed for the selected drug product?
3. Are any colorants used (none are permitted)?
4. Does the firm have written control procedures that adequately
describe the receipt, storage, sampling, issuance, and reconciliation of labeling and packaging materials? (per 21 CFR 211.122 - 130; 211.134 and 211.137).
5. Does the firm use cut or rol1 labels?
6. Are the labels similar in color, shape, size and format for different products or potencies?
7. Does the firm use any type of electronic label verification system (bar codes, machine vision systems, etc.)? Describe
8. Is the label verification on receipt, on line, or both?
9. Is any printing done on line of label text, lot number, expiration date, etc.?
10. Does the firm use dedicated packaging lines?
11. Are the samples of labels used for acceptance (proofing) of labels from vendors based on a statistical plan? Describe sampling plan.
12. Are labels printed by the firm or by an outside vendor?
13. Have these procedures been completely and accurately followed for the subject drug product?

14. Does the firm have an SOP on vendor audits?
15. Has the firm audited the (a) component, (b) container, (c) closure, and (d) label vendors? Report the dates of last audits.
16. Does the firm have written procedures for the production and process control of drug products? (per 21 CFR 211.100, - 211.115; 211.186; 211.188; 211.192)
17. Have these production and process control records been approved by the firm's quality control unit and by designated organizational units?
18. Have these process control records been completely and accurately prepared for the subject drug product?
19. Briefly describe the firm's procedures for changing any of the standard operating procedure documents described above.
20. Does the firm have written procedures for the review and approval of all drug production and control records before release of the batch for distribution? (21 CFR 211.192)
21. Were these procedures followed in the review of the selected drug product?
22. What are the firm's procedures for the investigation to be made following any unexplained discrepancy found in batch production records, or the failure of a batch or any of its components to meet specifications? (21 CFR 211.192)
23. Were these procedures followed accurately and thoroughly concerning any batch discrepancies/failures of the selected drug?
24. Does the firm have written laboratory control mechanisms, including change control procedures, which describe conformance to established specifications and standards for the selected drug product? (21 CFR 211.160-167)
25. Were all specified in-process and end product tests performed on the selected drug product?
26. Were all specifications met?

Monitoring of Environment
27. Is the air supplied to critical areas (exposed product/filling areas) filtered through HEPA filters under positive pressure?
28. Is the air flow in critical areas laminar when delivered to the point of use? At what velocity? Is velocity determined at the critical area or at the filter face?
29. How is the air filtered that is supplied to controlled areas (where unsterilized product, in-process materials, and container and closures are prepared)?
30. What are the firm's air quality classifications for:
a. exposed product areas
b. filling area
c. surrounding plant areas
31. Is room classification system based upon Federal Standard 209d or other?
32. Are HEPA filters efficiency tested?
33. How often are HEPA filters integrity tested? What test method is used?
34. How often are air flow velocities checked for each HEPA filter?
35. Does the firm have a written monitoring program for classified areas that included a scientifically sound sampling schedule that describes sampling locations, their relation to the working level, and frequency? Describe the basis for the sampling program. (21 CFR 211.160)
36. Are both viable and non-viable particulate samplings performed in all classified areas during production?
37. What is the frequency of viable sampling using "active" sampling methods for:
a. exposed product areas
b. filling areas
c. surrounding areas
38. What is the limits used, length of sampling period, and if sampling is done during production or at rest.
39. What is the type of viable sampling equipment use (STA, Centrifugal sampler, etc.)
40. Does the firm have data on the ability of these samplers to recover organisms without deleterious effect on survivability such as through impact or dessication of organisms or media?
41. What is the actual volume of air sampled per location.
42. Are settling plates used? Describe the length of exposure period; sampling frequency; location (including proximity to critical operations); microbial limits.
43. Are recovered microorganisms routinely identified? To what level (genus, species)?
44. Are the culture media used in the viable monitoring program shown to be capable of detecting molds and yeasts as well as bacteria by means of growth promotion tests? Is anaerobic monitoring performed?
45. What media are used?
46. Are deactivators (e.g., penicillinase) use for antibiotics or other bacteriocidal/bacteriostatic substances? Has the firm shown that these are effective? (Are records available? Are calculations correct?)
47. What incubation periods are used and at what temperature?
48. How often is non-viable particulate sampling performed in classified areas:
a. exposed product areas
b. filling areas
c. surrounding areas
49. What sampling device is used? What volume of air is sampled?
50. How many samples are collected per location? Are results averaged?
51. When was sampling equipment last calibrated?
52. Were environmental sampling results within specifications during the manufacture of the batches of the selected drug product?(any deviations and firm's response.)
53. How often is monitoring performed on filling room personnel?
54. What are the firm's alert and action limits for personnel monitoring?
55. What type of monitoring is done?
56. Does the firm have written procedures for the monitoring of product contact surfaces?
57. What type of contact surface monitoring devices are used (RODAC, swabs, etc.)?
58. Any changes in the air handling or environmental monitoring systems since the last EI? Were changes evaluated by management regarding the need for re-validation?

Part 1 Inspection and facility audit questionnaire for sterile dosage form

Also see

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What is a Laminar Air Flow Cabinet.

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Requirements of Building and Facilities for Sterile Dosage form , Injectables

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