1.  A central concept is that quality cannot be tested for! ◦ Testing programs are based on testing a statistically significant number of samples  However to be absolutely sure that all of your product meets specifications you would have to test everything. ◦ Testing by itself will not insure quality and is inefficient ◦ Testing is required under the GMP’s  Raw materials  In-process samples  Final Product ◦ Quality (identity, safety, efficacy, potency, purity, stability, consistency) must be designed into the production process ◦ Begins with predetermined specifications  Raw material specifications  In-process material specifications  Final Product Specifications

2. Validation – An Essential Part of GMP! Validation is the scientific study of a system  To prove that the facility/system/equipment/method is consistently doing what it is supposed to do (i.e., that the process is under control). ◦ We want to make decisions based on good science and not hunches and assumptions!  To determine the process variables and acceptable limits for these variables, and to set-up appropriate in-process controls. ◦ Is it ok if the wash from a chromatography column is pH 6.8 vs. 7.0 ?

3.  Biomanufacturing is a complex process involving multiple unit operations many of which are critical to insuring patient safety and product efficacy

4. Inoculum Seed Fermentation Production Fermentation Harvest Ultrafiltration 1 Chrom. 1 1 Ultrafiltration 2 Chrom. 2 Viral Filtration Chrom. 3 Ultrafiltration 3 Final Formulation/ Sterile Filtration Sterile Fill UPSTREAM DOWN- STREAM VIRAL NON-VIRAL Block Flow Diagram of a Typical Production Process

5.  A central concept in quality is that quality cannot be tested for. Quality must be designed and built into the production process.  Requires careful attention to raw material specifications, in process material specifications, and final product specifications.

6.  The FDA’s definition of validation: “Validation is a process of demonstrating, through documented evidence, that a process, procedure, method, piece of equipment, or facility will consistently produce a product or result that meets predetermined specifications and quality attributes.”

7.  Identity ◦ 21 CFR 211.84 (d) at least one test shall be conducted to verify the identity of each component of a drug product. ◦ Chemical, biological, immunological ◦ Raw materials, in-process intermediates, final products.  Safety ◦ 21 CFR 600.3 (p) safety as the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relationship to the condition of the recipient at the time.  Activity of active ingredients  Activity of the excipients or additives  Activity of process related impurities  Efficacy ◦ Effectiveness of the product in achieving its medicinal purpose (therapeutic, prophylactic, diagnostic). Gathered at Phase II and Phase III trials.  Potency ◦ 21 CFR 600.3 (s) specific ability or capacity of the product, as indicated by its appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner indicated to effect the given result.  Purity ◦ 21 CFR 600.3 (r) relative freedom from extraneous matters in the finished product, whether or not harmful to the recipient or deleterious to the product.  Cleaning Procedures  Stability ◦ 21 CFR 211.137 (a) to assure that a drug product meets applicable standards of identity, quality, and purity at the time of use; it shall bear an expiration date determined by stability testing. Drugs may use accelerated time studies, biologics must use real time studies.  Consistency ◦ The ability of the product and/or process to reliably possess specified quality attributes on an ongoing basis. 3 consecutive batches of product meeting predetermined specifications is accepted as proof that a process is consistent. However, in NDA data from up to twenty batches may be submitted.

8.  Validating the performance of unit operations, analytical methods, and critical process points (sterilization, viral inactivation, cleaning procedures) is essential in ensuring that the process generates a quality product.

9.  Assumptions concerning virus inactivation resulted in 1955 in ten deaths and 200 children becoming paralyzed in the US, from a supposedly “inactivated” polio vaccine.  Assumptions about sterilization caused severe infections among burn victims given supposedly sterile solutions.  Validation eliminates assumptions and relies on experimental proof!

10.  Validation does not replace testing, but it does reduce the testing burden for raw materials, in-process materials, and final product

11.  Validation itself is a process that evolves with the product.  Validation requirements for production of pre-clinical material much less stringent then for phase III clinical material.  Critical operations: raw materials, analytical methods, viral clearance, sterilization, cleaning.

12.  Some operations are more critical than others. ◦ Viral filtration, sterilization, cleaning, analytical methods. ◦ These operations will require greater validation efforts then less critical operations (media blending).

13.  How critical is the system being validated to final product quality? ◦ Media blending systems for cell growth vs. final fill & finish operations  Demonstrating that the device which fills, labels, and caps the final product will require more extensive validation then the blenders used to prepare media for bioreactors.  Validation of complex devices can take years!

14.  Proceeds in stages with new facilities / equipment.  Planning for validation should start with the design process.  Leaving validation to the last minute is asking for trouble.

15.  Starts with Design & Receipt: ◦ Does the equipment meet the needs (is the autoclave big enough?) ◦ Do you have the manuals, spare parts, can you plug it in? ◦ Is it installed properly (drain lines, vents, etc)  Does it work? ◦ Does the autoclave reach the necessary temp. and pressure? ◦ Can the autoclave sterilize your equipment (worse case situation)?  How does it work in the manufacturing process? ◦ Can it handle production quantities? ◦ Will failure compromise product quality?

16.  What parameters are critical to sterilization? ◦ Temperatures, pressures, time, pore size (filtration), radiation dosage, chemical concentration.  Must demonstrate that your autoclave reaches the temperatures, pressures, and times necessary for sterilization.  Must demonstrate that items representing real world samples achieve those conditions (20 ft of 1 ½ hose; a 20 L carboy; a 500 ml bottle).  Must challenge with worse case scenario (may take place in pilot plant if scalability demonstrated).

17. 21 CFR 211 Subpart F –Production and Process Controls  211.100 –Written procedures; deviations  (a) Requires written procedures for production and process control designed to assure that products possess the quality attributes that they purport or are represented to possess.  (b) Requires that any deviations from written production and process control procedures be recorded and justified.  211.101 – Change in of components  211.103 – Calculation of yield  211.105 – Equipment identification  211.110 – Sampling and testing of in-process materials and drug products  “Requires that control procedures be established to monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability of in process material and drug product.”  211.111 – Time limit on production  211.113 – Control of microbiological contamination  “Requires that sterilization processes be validated”  211.115 – Reprocessing 21 CFR 211 Subpart H- Holding and Distribution  211.165 – Testing and release for distribution  “Requires that the accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 21 CFR 211.194 (a)(2)” 21 CFR 211 Subpart I- Laboratory Controls 21 CFR 211 Subpart J – Record and Reports 21 CFR 820 Quality Systems Regulations

18.  Sec. 211.113 Control of microbiological contamination.  (a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.  (b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.

19.  A fully validated process is “locked in”  Any change outside of the validated space invalidates process  Change must be evaluated for effect on patient safety and product efficacy Validated Production Process Δ

20. Monitor RevalidateMonitor Validate Or Revalidate

21.  Specific protocols (SOP’s) that provide detailed information on what is to be validated.  Validation Protocols consist of: ◦ A description of the process, equipment, or method to be validated. ◦ A description of the validation method. ◦ A description of the sampling procedure including the kind and number of samples. ◦ Acceptance criteria for test results. ◦ Schedule or criteria for revalidation.

22.  Validation Protocols may consist of multiple SOP’s each describing specific steps in the validation process

23.  Starts with Design & Receipt: ◦ Does the equipment meet the needs (is the autoclave big enough?) ◦ Do you have the manuals, spare parts, can you plug it in? ◦ Is it installed properly (drain lines, vents, etc)  Does it work? ◦ Does the autoclave reach the necessary temp. and pressure? ◦ Can the autoclave sterilize your equipment (worse case situation)?  How does it work in the manufacturing process? ◦ Can it handle production quantities? ◦ Will failure compromise product quality?

24. Installation Qualification (IQ) A process used to document that the piece of equipment was supplied and installed properly and that appropriate utilities, i.e., electrical, steam, gas, etc. are available to operate the equipment according to the manufacturers specifications. Operational Qualification (OQ) A process designed to supply the documented evidence that a piece of equipment operates as it is intended through all anticipated operational ranges. Performance (Process) Qualification (PQ) Verifies that a process / piece of equipment performs as it is intended to in the manufacturing process and produces product (in process or final) meeting predetermined specifications.

25. Example of a protocol for the IQ component of validating a pH meter As with all other SOP’s this document will contain an Objective, Scope, and Responsibility Section.

26.  Name and description of equipment, including model numbers  Identification, including model and serial numbers  Location of the equipment  Any utility requirements, i.e. electrical voltage, steam or water pressure, etc.  Any safety features of the equipment, including alarms, interlocks, or relief valves.  That all documentation, including manufacturers contact information, spare parts inventory, operational manual, and installation drawings are available on site.

27. Example of a protocol for the OQ component of validating a pH meter As with all other SOP’s this document will contain an Objective, Scope, and Responsibility Section. O

28. Example of a protocol for the OQ component of validating an autoclave As with all other SOP’s this document will contain an Objective, Scope, and Responsibility Section.

29.  Objective  Responsibility  Equipment required (Calibration verification & Traceability)  SOP(s) used  Equipment Identification  Parameters measured (Specifications)  Documentation

30.  Ideally validation takes place prior to actual production runs, however in some cases validation may take place as product is produced, or past production runs may be used to provide validation data.  Prospective Validation  Concurrent Validation  Retrospective Validation

31. IQ OQ Calibration PQ protocol approval PQ protocol execution Data Analysis Validation Report Approve Conclusions

32. Are systems qualified? No Calibrations Correct ? Data Analysis Qualify system Calibrate system No Yes Approval

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34. Project Plan Agreed by team members Details phases, activities, and milestones Gantt Chart most commonly used

35. Putting it all together 35