Issues of a Large Multi-National Public Cord Blood Bank: Applying Pharmaceutical cgmpstandards to a Biological Model

Transcription

1 ISCT 7 th Annual Somatic Cell Therapy Symposium September 26-28, 2007 Issues of a Large Multi-National Public Cord Blood Bank: Applying Pharmaceutical cgmpstandards to a Biological Model Robert Chow, M.D., A.M. StemCyte International Cord Blood Center StemCyte, Inc.

2 Appreciations Organizing Committee ISCT AABB FDA CBER Disclosures Founder, Employee, Stockholder & Board Director of StemCyte, Inc. Board Director and/or shareholder of other biotech/drug companies and organizations unrelated to this talk.

3 StemCyte Cord Blood Banks Most racially diverse & second largest public CB bank Multi-national operations -currently in US and Taiwan with other locations planned HRSA NCBI & NMDP Bank, accredited by FACT and AABB Class 10,000 and 100,000 clean rooms planned as part of cgmp implementation Organizer of Annual International CBT Symposium & Editor of

4 Current Status of StemCyte Laboratory Our product differs from other CBB products because we only deplete plasma (minimally manipulated) and do not red cell deplete All product and processes thoroughly validated Outcome data is the ultimate assay for stability, purity and potency. Originally no specific FDA regulations governing Cord Blood Banks Followed standards for accrediting agencies & registries, e.g. AABB, FACT, NMDP.

5 cgmps Cover Safety, Purity, Potency, and Quality 21 CFR 211: cgmpareas Subpart B -Organization and Personnel Subpart C -Buildings and Facilities Subpart D -Equipment Subpart E -Control of Components and Drug Product Containers & Closures Subpart F -Production and Process Controls Subpart G -Packaging and Labeling Controls Subpart H -Holding and Distribution Subpart I -Laboratory Controls Subpart J -Records and Reports Subpart K -Returned and Salvaged Drug Products

6 Pharmaceutical or Biological Model - Which is more appropriate for cord blood? cgmps were originally written for the drug/ pharmaceutical industry. cgmps may apply a pharmaceutical standard to CB banks beyond that of other blood products. Is the pharmaceutical model a good fit for our existing cord blood industry? Blood Products are not treated strictly with pharmaceutical model.

7 Pharmaceutical or Biological Model - Which is more appropriate for cord blood? Why is Cord Blood not regulated as a Biological Product similar to Blood Products? Using these drug cgmp regulations will require expertise in areas currently not widely utilized within our industry such as QC Unit, Master and Batch Records Systems and Pharmaceutical Label Control.

8 Pharmaceutical Model Issues Pro Con Establishment of a QC Unit (QCU) Clean Room for cgmp Focused and dedicated approach to QC performance and tracking Rigorous & easy documenting control of aseptic manipulations International harmonization Responsibility and authority to approve or reject all components and drug products. May impinge on practice of medicine. May require more personnel for same tasks if QCU is truly independent.. Increased complexity & cost. No industry standard Label Control None Fits Biological model better ( ) Master and Batch Record Systems Better trackabilityand traceability Retrofitting current records and processes challenging Fits biologic model better. (600.3 (x) ; )

9 Establishment of a QC Unit (QCU) (Subpart B - Organization and Personnel) (a): The QCU has the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products. How do we reconcile this stance with the need for a Medical Director to supervise the medical practice aspects of a cord blood bank The Medical Director will head and supervise the QCU.

10 Establishment of a QC Unit (QCU) (cont) (Subpart B - Organization and Personnel) (b): Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the QCU. We interpret these regulations as requiring a separate QCU department; however, it may be possible to satisfy the requirements by sharing the QCU tasks within existing departments, e.g. QA and Operations.

11 Establishment of a QC Unit (QCU) (cont) (Subpart B - Organization and Personnel) Biological Model does not specify a QCU. Regulations are more general (c ): All records pertinent to the lot or unit maintained pursuant to these regulations shall be reviewed before the release or distribution of a lot or unit of final product. The review or portions of the review may be performed at appropriate periods during or after blood collecting, processing, compatibility testing and storing. In Biological Model, no requirement for QCU to have laboratory facilities to perform testing. Importance is placed on review, not who the reviewer is.

12 Requirements for a Clean Room (Subpart C -Buildings and Facilities) (c ): There shall be separate or defined areas or such other control systems for the firm s operations as are necessary to prevent contamination or mixups during the course of the following procedures: , (c ) (10): Aseptic processing, which includes (goes on to define what is meant by aseptic processing.) Does aseptic processing automatically mean a clean room?

13 Requirements for a Clean Room (cont) (Subpart C -Buildings and Facilities) Procedures (e.g. aseptic connection) that expose a product or product contact surfaces should be performed under unidirectional airflow in a Class 100 (ISO 5) environment. The environment of the room surrounding the Class 100 environment should be Class 10,000 (ISO 7) or better. * * In Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Appendix 3:

14 Requirements for a Clean Room (cont) FDA has stated that clean rooms are not specifically required to achieve cgmpand has not specified what room classification is needed; however, environmental monitoring, HVAC and establishment descriptions are still required, so what are the acceptable parameters? Is a clean room needed for certain types of closed systems? What constitutes a closed system? Use of sterile docking? Sample handled aseptically under the hood? Reagents added under the hood? If yes in some situations, what is the class of clean room required? Type of air handlers? # air exchanges per hour? pressure differentials? Is it as described, class 10,000 (ISO 7)? If not, what is required?

15 Requirements for a Clean Room (cont) Does EU have or will have requirements for clean rooms? Without a clean room, sampling and sterility testing alone may not adequately ensure sterility and lack of contamination. Some of the processes and environmental monitoring that are required by cgmpare simply not easily achieved without a clean room We interpret these regulations to strongly support the use of a Clean Room at StemCyte, and are moving in that direction.

16 Label Control Subpart G -Packaging and Labeling Controls Label Control requires accounting for every label that we produce as well as containers. Is collected CB considered an intermediate product? Yes. Is the FDA going to determine CBB as having more than one product code? This affects how we conduct label control. Line clearance will need to clear the line for each different product.

17 Label Control (cont) Subpart G -Packaging and Labeling Controls Pharmaceutical control of labels and containers is very strict and set up for a pill bottle model, but may not appropriate for CBB. A large blood bank operation has interpreted Biologics Label Control ( ) by having secured storage (bulk supplies) and controlled storage (working stock for shelves).

18 Stability Assays Subpart I -Laboratory Controls (a): The results of such stability testing shall be used in determining storage conditions and expiration dates (b) there must be stability studies conducted including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration data determined. Ongoing stability program can rely partially on in vitro and surrogate testing assays. Older units being transplanted provide opportunities to monitor changes in outcome data to assure that ongoing processes at established programs remain robust.

19 Master Productions and Control Records Subpart J -Records and Reports Pharmaceutical CFR references previously not applied to CBB manufacturing and may not be descriptive (b)describes the content of these records: Name, strength, dosage, active ingredient, total weight of dosage unit. Components, weight of each component, excess of component Theoretical weight at appropriate phases of processing Description of containers, closures, packaging materials, Copy of each label signed and approved. Complete manufacturing and control instructions, specifications, etc.

20 Master Productions and Control Records (cont) Subpart J -Records and Reports covers Standard Operating Procedures covers Records and Reports Too detailed to show complete regulations, but procedures and records described are more similar to cord blood than items listed on previous slide.

21 Batch Production and Control Records Subpart J -Records and Reports Definitions. (2) Batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture. (10) Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.

22 Batch Production and Control Records (cont) Subpart J -Records and Reports (x): Lot means that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel. Pharmaceutical definitions unnecessarily complex for this model.

23 Requirement for Environmental Impact Assessment (21 CFR 25) An Environmental Impact Assessment (EIA) is required as part of NEPA (National Environmental Policy Act of 1969 ) The EIA shall focus on relevant environmental issues relating to the use and disposal from use of FDA-regulated articles and shall be a concise, objective, and well-balanced document that allows the public to understand the agency's decision.

24 Requirement for Environmental Impact Assessment (EIA) It does not appear that CBB operations meet any of the Categorical Exclusions provided by NEPA and thus licensure applications will likely require professional prepared EIAs. Licensure applications may require EIAs of currently existing operations retrospectively.

25 Conclusion FDA has done an excellent job in drafting guidance to regulate a complex, new & rapidly changing industry. Agrees flexibility is needed Shifting an existing cord blood bank operation from a Biologic cgmp Model to a Pharmaceutical Model will be a challenge The key will be to fully understand the differences and develop flexibility within an organization to see a new way of accomplishing the same thing.

26 Organizers ISCT AABB FDA Robert Chow, M.D., A.M. Laura Gindy, MT, SBB, CQA (ASQ), D. Matt McCarter, MT, Paul Heinze, MS, MT, Char Connor, MS, MT, Connie Heflin, MT, Allen Lin, Judy Kang, Wendy Chan, RN, RMW, Dee Thumwanit, RN, Brian Wang, MS, Richard Brown, MS, MT, & Lawrence D. Petz, M.D. StemCyte International Cord Blood Center StemCyte, Inc.

27 The following slides are unrelated to facilities issues and will NOT be presented during this Session. They are included in the Work Book for Informational Purposes Only, and will NOT be subjected to discussions by the Panel or the FDA

28 1. Processing Recommendation Draft guidance Sect VII, 10, b, We recommend that your manipulation of the cord blood be restricted to volume reduction by depletion of red cells and plasma, followed by cryopreservation. We disagree with this stance for recommending red cell depletion over other established methods, such as plasma depletion or whole CB, as this position is not supported by current clinical data. Considerable clinical outcome data of CBT using plasma depleted CB products that are not red cell depleted/reduced, which are just as good if not better than red cell depleted/reduced products.

29 Audited Outcome of Unrelated CBT with Plasma Depleted CB Product ANC 500 Engraftment C.I. (Median 22 days) 88±4% Platelet 20K Engraftment C.I. (Median 49 days) 69±4% Platelet 50K Engraftment C.I. (Median 62 days) 64±4% 1-Yr Relapse Rate 23±3% 100-Day TRM 17±2% 1-Yr TRM 28±3% 1-Yr Overall Survival 61±3% 1-Yr Disease Free Survival 51±3% Audited by CIBMTR on site at transplant centers with 97.3% accuracy. N=309; 70% malignant-ibmtr classification early 27%, intermediate 40% & advanced 34% of cases with known disease status StemCyte Resolution: Submit Master File of Outcome Data of CBT using Plasma Depleted Products to the FDA

30 2. Demonstration of Comparability How to ensure that cord blood manufactured under new processes or previously manufactured cord blood that met earlierefficacy and safety standards are available to patients & transplant centers Clarification of demonstration of comparability Purity & Potency Assays Evaluation of New Processes or Technologies Demonstration of product to product reproducibility and lack of variability Pharmaceutical Definition: Potency therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard) [21CFR (16) (ii)] Biologics Definition: Potency the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended to effect a given result. [Biologics 21CFR600.3 (s)]

31 Comparability Methods Clinical Evidence - Engraftment, TRM, GvHD, Relapse, OS, DFS, Adverse Reactions CFU/ Animal Models CD34+ TNC Pros Gold standard the most rigorous way to truly ensure comparability of processes Best surrogate marker for stem cells & marker for progenitor cells No CFU growth correlates with graft failure Easy to perform Better outcome correlation Easiest to standardize Most established surrogate marker for outcome Cons Time consuming years May hinder innovation Confounding factors Need large sample size, retrospective matched pair or prospective studies Not marker of stem cells Difficult to standardize in vitro artifacts Time consuming - weeks Not marker of stem cells Difficult to standardize Worst clinical correlation Not marker of stem cells

32 Clinical Outcome - Gold Standard for Comparability Changes in clinical outcome (engraftment, survival, GvHD, relapse, TRM) by using new processes cannot be predicted from in vitro assays or animal models, e.g. ex vivo expansion, plasma depletion, double cord, post-thaw wash Adverse Reactions cannot be predicted from in vitro assays or animal models In vitro assays are subject to artifacts of assay designs, e.g. low CFU with cord blood products that have high red cell %, CD34+ with gating or methodologies

33 Post-Thaw Wash for plasma depleted CB Rationale: Reduce osmotic shock, removal of DMSO & red cell ghosts/free hemoglobin* However, unwashed cryopreserved hematopoieticand cord blood cells have been used clinically for years by many centers with satisfactory results & comparable adverse reaction rates** What is the evidence that post-thaw wash is actually beneficial or at least harmless for plasma depleted CB and are in vitro assays predictive? What is the clinical evidence that not washing causes more adverse reactions for plasma depleted CB? *Rubinstein et al. PNAS :10119; **Chow et al. BBMT in press, Blood :405b; Stiff et al. Blood 106:580a; Hahn et al. BMT :145; Nagamura-Inoue et al. Transfusion :1285; Larocheet al. Transfusion :1909

34 Actual Thaw Data for PD CB from Transplant Centers Can these in vitro assays predict clinical outcome? N = 217 PD CB (102 NW & 115 W) Recovery of Pre-Freeze Cell Dose in Infused Cell Dose NOT Post- Thaw Washed PD CB (n=102) Post-Thaw Washed PD CB (n=115) Avg. NW/W Ratio Median NW/W Ratio Twosample T-test p-value Pre-Freeze TNC (10 7 ) Infused TNC (10 7 ) % Post- Thaw TNC Recovery 158 Mean 173 Mean Mean 132 Mean % Mean 84% Mean

35 Cumulative Incidence of Engraftment Neutrophil (ANC500) Engraftment by Wash Status (n=276) No wash (n=132) % Wash (n=144) 87 5 % Median Engraftment Time: No wash - 21 days Wash - 27 days (6 days slower) Log-rank: P = Months Post-Infusion

36 Platelet 50K Engraftment by Wash Status (n=252) Cumulative Incidence of Engraftment No wash (n=116) 73 6 % Wash (n=136) 59 5 % (14% lower) Median Engraftment Time: No wash -55 days Wash -71 days (16 days slower) Log-rank: P = Months Post-Infusion

37 Univariate & Multivariate Analysis* Current in vitro assays cannot predict these results Univariate ANC 500 Plt 20K Plt 50K 1 Yr Relapse 3-Yr NRM 3-Yr OS 3-Yr DFS Wash 87±5 64±5 59±5 27±5 38±5 48±4 30±6 No Wash P value Multivariate RR Wash = 1.00 RR No Wash 91± ANC ± Plt 20K 73± Plt 50K 20± Relapse 23± Nonrelapse death 67± Death 57± Death/ Relapse P value *Adjusted via Cox Regression for malignancy, TNC dose, single vs. double cord TX, HLA matches, recipient sex, & age. (278 cases had complete records started with all 285 patients.)

38 GvHDof Post-Thaw Washed vs. Not Washed PD CB Current in vitro assays cannot predict these results. GvHD Washed Not Washed P value Grade II-IV agvhd Grade III-IV agvhd Limited cgvhd Extensive cgvhd 36% (n=137) 15% (n=137) 9% (n=117) 17% (n=117) 36% (n=113) 14% (n=113) 36% (n=77) 1% (n=77) < Similar results and p values were observed using multivariate analysis and matched pair studies (p=0.001) Relapse rate for NW was not higher than that of the W group.

39 StemCyte Comparability Recommendations - Purity & Potency Assays for New Processes Need to balance innovation, safety & efficacy Novel processes without clinical outcome validation can get IND with in vitro assays/animal model data CIBMTR SCTOD will collect, analyze & monitor outcome of new processes/programs Once sufficient outcome is available to make meaningful statistical comparisons with current processes, can decide whether to abandon or allowed to continue.

40 StemCyte Comparability Recommendations - for Monitoring of Existing Operations Need to balance practicality, safety & efficacy Ongoing QA/QC program can rely on in vitro assays CIBMTR SCTOD will continuously collect, analyze & monitor outcome of program Changes in outcome or trends in programs need to be monitored to make sure that ongoing processes at established programs remain robust.

41 StemCyte Comparability Recommendations - Stability Assays Determine Expiration Date (ED) by appropriate stability testing (Guidance, Sect. VII, B, 11, d reference (a)) Routinely, stability program can rely partially on in vitro and surrogate testing assays. Transplantation of older products provide opportunities to monitor changes in outcome data by QC Unit to assure stability, i.e. the older units have not lost potency. Stability Testing ( (b)) supports the concept of a tentative ED. When tentative date is beyond date supported by actual shelf life studies, keep conducting studies until tentative ED is verified or appropriate ED determined. Allows indefinite ED?