Quality Systems

Facilities Maintenance and Controls
Controls over Organization and Personnel
Equipment Maintenance and Controls
Raw Materials Controls
Production and Process Controls
Environmental Monitoring
Packaging and labeling Controls
Holding and Distribution Controls
Laboratory Testing Controls
Records, Documents and Change Controls
Corrective and Preventative Action Programs
Independent Quality Assurance
Issues/Questions

C.3.1. Facilities Maintenance and Controls
Access to the facility is primarily controlled by ID swipe cards and is limited to authorized personnel. All production equipment, and product storage or holding containers are located in the facility and accessible only to personnel authorized to enter the facility.

To prevent any product cross-contamination only one product is manufactured or processed at a time. The facility and all equipment is broken down and cleaned/sanitized between products. If more than one batch of the same product is being manufactured then the start of each new batch is set approximately one week from the start of the previous batch. Each batch is then at a different stage of production at any given time. The four separate Class 10,000 production suites are then used to maintain spatial and physical separation of individual batches. Production staff do not work on more than one batch at a time.

Regular cleaning of the facility is performed weekly under contract by MaintainIT Ltd., an organization with experience cleaning facilities for clients such as Biogen, Glaxo Smith Kline, Novartis and Pfizer. Facility personnel follow additional SOPs for cleaning Class 100 cabinets before and after each use, and for monthly incubator cleaning, including chemical treatment and steam sterilization. Other cleaning and sanitation SOPs cover all other types of cleaning or sterilization required.  Certain key pieces of equipment that may come in contact with products are sterilized using validated autoclaves or ethylene oxide gas at the UNC Neurosciences Hospital.

Class 10,000 air is provided by HEPA filtration and is monitored on a continual basis during production with total air particle counters as part of the Environmental Monitoring program.   

C.3.2. Control over Organization and Personnel
The JVL has an Organizational Chart that clearly describes the Chain-of-Command.  Dr. Jude Samulski is the Director of the UNC Gene Therapy Center and oversees all operations associated with the Center.  The Director of the JVL is Dr. Jeffery Beecham who was previously with the Harvard Vector Core.  Dr. Beecham oversees all aspects of the facility and its operations. This includes Quality Systems management, preparing and releasing SOPs, scheduling productions, reviewing production and testing records, and investigating problems and/or deviations.  Dr. Beecham reports to Dr. Samulski.  Ms. Angelique Camp is the Lab Manager for the Clinical Wing of the JVL and is responsible for overseeing all day-to-day operations and for ensuring that standard procedures are followed.  Ms. Camp reports to Dr. Beecham.  Up to four Production Technicians work under Ms. Camp and are responsible for producing vectors.  The technicians report to Ms. Camp.  The responsibilities of managers, staff, and QA are clearly described in the SOPs that cover each type of activity.

All personnel undergo general training in cGMP on an annual basis.  Training on specific SOPs is performed using a two step review and performance evaluation process.  Training is documented for each applicable individual as both “Read and Understood” and “Performed and Observed”.  Production and QC personnel have extensive hands-on training in the manufacture and testing of rAAV products. Dr Beecham performs training as required for specific processes, new SOPs, and annual cGMP training.  Ms. Camp provides hands-on training for new employees.  Training records are maintained and controlled by QA.

C.3.3. Equipment Maintenance and Controls
All production equipment is numbered and recorded in an Equipment Log that is used to identify and describe each piece of equipment.  All equipment is entered into an equipment maintenance and calibration database which is used to schedule equipment maintenance and calibration.  Equipment is scheduled for preventative maintenance and calibration on an annual or semi-annual frequency depending on the specific piece of equipment.  Additional equipment logs are issued for each piece of equipment and are used to maintain a chronological record of equipment maintenance, repairs, calibration, or other equipment events.  The cleanliness of equipment is maintained through weekly cleaning, breakdown cleaning between productions, and special cleaning procedures when necessary.  Temperature controlled storage containers are monitored daily whenever they are in use with NIST-traceable thermometers.  Monitoring data is recorded on equipment monitoring log sheets.

C.3.4. Raw Materials Controls
All raw materials, components, and closures used for production are identified and qualified using a Raw Materials Specifications program. Master documents are filed for each type of raw material specifying the acceptable vendors and qualities of the materials that can be used.  The receipt of all raw materials is recorded on material receipt data sheets and stored in slave files for each type of material.  All materials are visually inspected and any identity tests are performed prior to acceptance and their acceptability is recorded in the slave file.  Damaged or incorrect materials are discarded or transferred to the research laboratories.  Raw materials are then labeled as either released or quarantined and released materials are stored separately under lock and key access.

Specification records are also used for any formulations that are prepared for production or testing.  Formulation documents include material and equipment specifications, formulation instructions, and sections to record actual preparations, equipment used, and any testing that is performed.  Separate records are kept for each lot of any formulation that is prepared.

Materials and formulations that will be directly used in a specific production lot are transferred into the Class 10,000 rooms or appropriate storage containers in the facility and are held there during production.  The lot numbers of all raw materials transferred into the facility for use are recorded in the batch records for that specific product.  Once production is completed any leftover materials are discarded or transferred to the research laboratories.  The facility then undergoes a complete cycle of breakdown cleaning and re-stocking to prepare the facility for production of the next product.

C.3.5. Production and Process Controls
All production and process controls are specified and described in the SOPs that cover each specific method, procedure, or control mechanism.  The written procedures for these controls are primarily elaborated in the 2000-series of SOPs in the attached SOP list (see Appendix A).  Documentation that the procedures have been followed is recorded in the batch records for the specific product being produced.  These records include; labeling requirements, calculations performed during production, recording which equipment was used and for how long, the results of any In-Process tests that are performed, and records on the Date/Time on which procedures were performed.  All sections of the batch records are recorded by one person and verified by a second person.  Any non-disposable containers that may come in direct contact with the product are sterilized in the validated autoclaves and/or ethylene gassing services provided at the UNC hospitals.  Any deviations from proscribed procedures or problems are documented using Quality Variation Reports.  

The Facility currently has SOPs released for the production of clinical-grade AAV and Adenovirus, clinical lots of cell-based vectors, and cGMP products for use in further manufacturing such as cell lines and DNA plasmid molecules. The JVL is currently developing the SOPs for production of AAV in Baculovirus.

C.3.6. Environmental Monitoring
The Environmental Monitoring (EM) program includes testing for total airborne particulates, viable airborne particulates, surface contaminants, and personnel monitoring performed periodically during production and at all final fill operations.  EM testing includes;

• Total Air Particle Testing utilizing Met One Particle Counter
• Viable Air Particle Testing using the RCS Plus System
• Viable Air Particle Counts using Settling Plates
• Viable Surface Counts using RODAC Touch Plates
• Dynamic and personnel monitoring performed during all Final Fill operations

The facility staff, QA, and the Lab Director hold integrated responsibilities for EM and EM review procedures during both Start Up, and In-Process periods.  If measurements exceed the specifications set for alert and actions limits in the EM SOP, special cleaning procedures and/or investigations are undertaken.  Bioburden is then re-assessed and any further corrective actions are undertaken.

C.3.7. Packaging and Labeling Controls
Acceptable packaging materials are specified using Raw Material Specification sheets, and are autoclaved prior to use in a validated autoclave.  QA maintains control over all labeling materials and is responsible for preparing and issuing labels and for accounting for returned and unused labels.  Labels are then transferred to the Lab Manager who checks each label individually for accuracy.  An inspection of the labeling area is performed prior to labeling each lot or sublot and all unused labels are retained and returned to QA after labeling is completed for QA accounting purposes.  At least two individuals who are directly involved in filling operations are responsible for checking all labeled containers individually and for verifying that the information on the container corresponds with the materials being filled.  If sublots are being prepared, then labeling and fill operations are carried out independently for each sublot, and the labeling and filling areas are cleared and re-inspected between sublots. 

Accounting is performed on the vector material that is used for filling by reconciling the starting material with the amount filled, the amounts lost or discarded, and the amount remaining after filling.  If more than one production batch is pooled to provide adequate quantities of vector for a specific fill, then a separate Batch Record is prepared to record the individual lots used for the pool and the filling of those lots into a single new lot of material.  Any lots used for pooling are pre-tested for sterility and other applicable safety tests prior to pooling and the final pooled lot is re-tested after final fill.    

C.3.8. Holding and Distribution Controls
Finished products are stored in temperature freezers and the freezers are monitored daily to ensure temperature limits are not exceeded.  The storage of clinical-grade products is recorded in freezer logbooks.  The removal of individual vials of test-articles or the transfer of vials to clinical sites is recorded in these logbooks.  Products are not released until all Lot Release testing has been performed and the results have been reviewed to make sure all specifications have been met.  Retention samples are stored under the same conditions as patient-use vials.  Additional holding, storage, and distribution controls for used for tracking test article samples and shipping of clinical products. 

C.3.9. Laboratory Testing Controls
For each lot of clinical material, a Product Specification Record is created that specifies each type of test to be performed, the testing method or protocol number, the type of material to be sampled (e.g., unprocessed bulk, purified material, etc.), and the acceptability criteria.  This document is then used to determine the type, amount, and number of test-article and retention samples to be taken.  

All Safety and Sterility testing is performed according to cGLP regulations by contract vendors such as AppTec and BioReliance.  Testing protocols are reviewed for methodological specifications and if acceptable are then authorized by the Laboratory Director.  Test results from contract vendors are reviewed by the both the Laboratory Manager and the Lab Director to determine if the results meet product release criteria. 

Purity and Potency testing is performed at the UNC Vector Laboratories (“In-House Testing”).  In-House Testing is performed in lab space dedicated to quality control testing.  All tests are described in test-specific SOPs.  In-House Testing is performed under the same Quality Systems controls as those used for cGMP manufacturing.  Test results from all In-House Testing are reviewed by the Laboratory Manager, Lab Director, and the GTC Director.       

The Product Specifications and the test results are then compared and if all tests meet specifications then a Certificate of Analysis (COA) is prepared which fully describes the characterization of the material.  The COA is reviewed and signed by the Lab Director and QA and the product is then eligible to be released.  Copies of the Production Specifications, COA, and all Original copies of all test results are maintained with the completed Batch Records.

C.3.10. Records, Documents and Change Controls
QA and the Laboratory Director are responsible for maintaining and archiving all log books, Batch Records, data sheets, and any other records associated with the facility and its operations.  All documents have identifying numbers and have an effective date hand written on them.  Originals are hand stamped with the statement “Controlled Document Do Not Copy.  QA is responsible for making copies of documents and issuing them to the staff as necessary.  Records are reviewed at least annually by both the Laboratory Director and QA.

Changes to SOP’s are made by the Lab Director or his designee and then submitted to QA for circulation to all applicable staff members for comments.  Once any corrections or comments have been made, the SOP is given a new number and effective date and then released.  QA is responsible for replacing superseded SOPs in the Master and Working SOP Manuals and for archiving old SOPs.

Other changes to facilities or its operations are made according to SOPs for either “Permanent Change Controls”, or “Temporary Change Controls”.  The person requesting the change obtains a change request form from QA, completes the form, and returns it to QA.  The change request is reviewed by QA and/or the Lab Director and the then authorized or denied.  Chronological logs are maintained for all change request forms issued.  Temporary changes are allowed for a two week period, two batches of the same material, or two successive occurrences whichever comes first. 
   
C.3.11. Corrective and Preventative Action Programs
Deviations from proscribed procedures are documented in Quality Variation Reports (QV).  The person who identifies a deviation requests a QV report form from QA.  QA puts an identifier number on the form and records it issuance.  The requestor records the nature of the deviation and any other information regarding when it occurred, causes, and products or equipment involved and then returns the form to QA.  QA and the Laboratory Director then investigate the deviation and determine its impact on quality, the appropriate action to take in response to the specific deviation, and any corrective action to take to prevent similar occurrences in the future.  The results of the investigation, the decisions made, and their justifications and then recorded in the QV report.  QA then schedules the performance of any corrective actions and records their completion on the QV.  After final review by QA and the Laboratory Director, the QV is signed and filed in a QV log book.

C.3.12. Quality Assurance Audits 

C.3.12.1. Internal QA Audits
Internal QA audits will be performed by the QA officer, Ms. Lori Nisi on at least an annual basis.  These audits will include a review of all documents associated with the production of vectors for that year, a review of the Quality Systems and their effectiveness in maintaining control, a review of all Quality Variations and how effective the corrective actions have been, and a review of all SOPs.  A written Audit Report will be prepared by QA describing any shortcomings identified during the audit.  The Audit Report will be submitted to Dr. Beecham and Dr. Samulski for review.  The Lab Director will then prepare a written response to the audit and provide mechanisms and a schedule for correcting any problems.  QA will then monitor the performance of any corrective actions taken and recommend additional corrective steps if necessary.  The audit report and the response will be maintained in a permanent Internal Audit file by QA.  The QA officer will also perform internal investigations or audits at any other time if deemed necessary.

C.3.12.2. External QA Audits
The facility will have external QA audits performed on at least an annual basis.  A permanent file will be maintained recording the performance of these audits, the problems identified, and the actions taken to correct any problems.  External QA audits will be performed at least annually and will be done by Dr. Andra Miller from Biologics Consulting Group, and Phil Cross at PC Associates.  External QA audits will be done on an alternating rotation between Biologics Consulting Group, and PC Associates in order to expand the scope of issues examined.  Audit Reports, responses, and reviews will be prepared as in Section C.3.12.1 above.  QA will oversee the performance and completeness of any corrective actions taken as a result of external audits.
 
C.3.12.3. Audits Performed by the CVL on External Contactors and Vendors
The JVL will conduct audits of key contactors and vendors through either site visits and/or by phone.  The JVL will also perform audits of clinical sites that receive JVL vectors if the vector will be used for further manufacturing.  The goal of these audits will be to assist clinical sites maintain adequate controls during any further manufacturing steps.  Ms Nisi will conduct these audits with the assistance of Dr. Beecham.  A record of these audits will be maintained by QA.