1. M ODULE 8 – Q UALITY S YSTEMS IN A P RODUCTION L AB Shelley O’Grady, M.S. Associate Professor, Biotechnology Dept. Austin Community College

2. O BJECTIVES – A T THE END OF THIS WORKBOOK THE STUDENT SHOULD BE ABLE TO : Identify the necessary components for a quality system laboratory. Describe the issues relating to resources in a GMP compliant manufacturing facility. Describe what is required for specifications concerning products, processes, and resources when establishing a process. Describe the proper procedure for dealing with an out-of-specification event. Explain the importance of validation and how it is utilized in a GMP compliant company.

3. G ENERAL P RINCIPLES AND L ABORATORY M ANAGEMENT Three keys to good company-wide quality control: 1. Trained personnel with the required skills. 2. Clear designation of each person’s responsibilities. 3. Adequate supervision.

4. Q UALITY S YSTEMS IN THE P RODUCTION F ACILITY Facilities and Equipment 1. Basic Contamination : Sterile and unsterile materials should be stored separately. 2. Cross-Contamination : Finished products ideally should not cross the paths of raw materials because of the possibility of confusing them or contaminating the finished product. 3. Environmental Contamination : There should be a well-thought out housekeeping program to keep the facility clean, free of rodents and other pests, and monitored environmentally in line with regulations and the appropriate standards.

5. Q UALITY S YSTEMS IN THE P RODUCTION F ACILITY Handling Raw Materials It is essential not to confuse or mislabel Raw materials intended for production should not be released to production until they have been tested Storage conditions should take into consideration hazards associated with the material, perishability and temperature and humidity requirements. Traceability of materials must be assured

6. Q UALITY S YSTEMS IN THE P RODUCTION F ACILITY Specifications Manufacturer’s specifications describe properties that are important for that product based on its intended use. The specifications for the same property may vary depending on the intended use. Specifications always are associated with analytical methods. Note that specifications are based on intended use.

7. P ROCESSES AND O UT OF S PECIFICATION (OOS) When an OOS result occurs the analyst must perform the following steps: 1. Analyst should immediately inform lab supervisor. 2. The analyst and supervisor must conduct and information lab inspection including: reviewing analysts’ notebooks/worksheets/calculations, examining instruments used and discussing test procedure and analyst training/ competency. 3. The analyst and supervisor must document the investigation results, recording any errors that might have been uncovered and any conclusions that were reached.

8. C HANGING C ONTROL P ROCEDURES Guidelines for change control procedures include, but are not necessarily limited to: 1. Review and approval of the (proposed) change 2. Verification of completion of required studies, reports, etc., supporting the change. 3. Good documentation of all events surrounding the change. 4. A change control file that includes documentation of approvals, a history of change for each official document, and records and data to support the change.

9. D ESIGNING A GMP- COMPLIANT P ROCESS The following is a brief summary on how to design a process: 1. The purpose of the process must be defined, that is, the desired output must be determined. 2. An endpoint (s) that demonstrates that the process has been performed satisfactorily must be defined. 3. A method to measure the desired endpoint is required. 4. Raw materials and their specifications must be established. 5. The steps in the process must be determined, usually by experimentation. 6. The process must be scaled-up for production.

10. D ESIGNING A GMP- COMPLIANT P ROCESS 7. An analysis of potential problems must be performed, noting the “critical points”. 8. Experiments must be performed to determine how the process must operate at each critical point in order to make a quality product. 9. Methods to monitor the process must be developed. 10. Methods to control the process must be developed. 11. Effective record-keeping procedures must be developed. 12. All SOPs required for the process must be written and approved.

11. V ALIDATION OF P ROCESSES AND A SSOCIATED E QUIPMENT Process validation is the action of proving, in accordance with GMP, any procedure, process equipment, material, activity, or system actually leads to the expected results. Process validation is defined by the FDA as “ establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.” Validation and GMP are inseparable and are essential parts of quality assurance.

12. V ALIDATION OF P ROCESSES AND A SSOCIATED E QUIPMENT Calibration is a process that compares a known (the “standard”) against an unknown (device in question). Verification is simply the process of “verifying” that a device is in tolerance (within acceptable range). Validation is a detailed process of confirming that the instrument is installed correctly, that it is operating effectively, and that it is performing without error. Validation is broken into three different tests: the installation qualification (IQ), the operational qualification (OQ), and the performance qualification (PQ).

13. V ALIDATION OF P ROCESSES AND A SSOCIATED E QUIPMENT Validation can be divided into three parts: Installation Qualification (IQ): Documented proof that the building, wiring, installation and calibration of equipment, utilities, SOPs, spare parts and specifications meet the design intention. Operational Qualification (OQ): Documented proof that the system (i.e. maintenance log review, raw and process water systems, pure and process steam systems, process gases…) performs as specified. Performance Qualification (PQ): Verifies that facility, equipment or systems operate as intended under challenge conditions. Depending on equipment, equipment PQ may be performed concurrently with process validation of product.

14. V ALIDATION OF P ROCESSES AND A SSOCIATED E QUIPMENT The planning of validation occurs throughout the development of the product. Validation begins with an understanding of the process to be validated, how the process works, and what can go wrong. The actual validation of a process does not occur until the process is in place. Validation requires a validation protocol, which is a document that details how the validation tests will be conducted.

15. T HE COMPONENTS OF A VALIDATION PROTOCOL 1. A description of the process to be validated. 2. An explanation of the features of the process that are to be evaluated. 3. A description of the equipment, raw materials, and intermediate products that are to be evaluated. 4. An explanation of what samples are to be collected and how they are to be selected. 5. Procedures for the tests and assays to be conducted on those samples. 6. An explanation of how the results of the assays are to be analyzed (including statistical methods). 7. A statement as to how many times each test is to be repeated. 8. SOPs describing how to run the process.

16. V ALIDATION - U NPLANNED O CCURRENCES Even in the most carefully designed facilities, however, unplanned occurrences do happen. Unexpected occurrences are called deviations Typically, the validation plan will have a form for documenting the deviation. The supervisor and the quality department will review the deviation to determine the plan of action to correct the deviation. Along with the deviation, the corrective action is also carefully documented and implemented.

17. V ALIDATION - U NPLANNED O CCURRENCES Nonconformance is a term used to describe a final product or raw material that has fallen out of specification. When a product or raw material is nonconforming, it is quarantined until a thorough investigation is completed and a decision of outcome made by the quality department. Sometimes the outcome will result in a final product being reprocessed or even destroyed. Raw materials are typically returned to the vendor.

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