Current good manufacturing practices: application to the processing of hematopoietic cell components

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Cytotherapy (2000) Vol. 2, No. 1, 59–62

Current good manufacturing practices: application to the processing of hematopoietic cell components SD Rowley Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Introduction Current good manufacturing practice (cGMP) regulations continue to arouse the interests of those involved with the production (manufacturing) of hematopoietic stem cell (HSC) components. In part, this interest results from the development by professional societies of standards for collection and processing centers, and the inspection and accreditation process derived from those standards. In part, this also results from the increasing regulations that the United States Food and Drug Administration (FDA) is applying to cellular and tissue-based products. These actions by FDA and professional societies established a minimum standard for the production of hematopoietic stem cell components. But, the application of these standards to an individual laboratory involves some amount of judgement complicated by an evolving regulatory environment. Thus, the laboratory worker faces the challenge of interpreting a changing set of rules and applying these rules to the changing laboratory practice. Many HSC processing laboratories have attempted to establish a ‘GMP’ facility with the expectation that this will ensure compliance to the many regulations that apply or will soon apply to the laboratory. But cGMP is not a facility – rather it is a philosophy of manufacturing similar to other quality assurance programs intended to minimize lot-to-lot variability in the production of drugs and biologics. Consistency, potency, and purity are characteristics of optimal HSC components regardless of the level of processing performed. Clinical research loses value if the HSC components are not consistent in achieving engraftment or other endpoints of the study. A well-defined manufacturing pathway for each type of HSC component manufactured should be the goal of each facility. These

pathways will vary between facilities because even simple components such as PBSC that are cryopreserved for autologous transplantation are collected and processed using techniques and reagents unique to each facility. Different cytokine doses, apheresis devices and techniques, and cryopreservation supplies and techniques lead to a myriad permutations of this otherwise simple process. The ideal quality plan, therefore, will be one that provides an infrastructure for the manufacturing pathway while still allowing for the production of different products.

GMP defined What are current good manufacturing practices and why are these codified in the Code of Federal Regulations (CFR)? cGMP regulations were written by FDA to ensure the manufacturing of drugs, biologicals, and devices of uniform purity, potency, and efficacy. A guiding principle of drug manufacturing is that the prevention of contamination is much simpler than the removal of contaminants. This is especially true for biological products such as HSC components. By nature, the exact compositions of biological products are difficult to define. Moreover, biological products are easily contaminated and difficult to purify. If we accept these statements as true, it is easy to recognize the importance of developing a well-defined manufacturing pathway that prevents the introduction of adventitious agents. Certainly, facility design is an important component of the manufacturing pathway. Statements illustrating that intent in the regulations are easy to find in the CFR and other documents published by FDA. For example, FDA requires for biological production facilities that, ‘. . . all work with spore-bearing microorganisms shall be done in an entirely separate building . . .’ [1] and that,

Correspondence to: Scott D. Rowley, MD, FACP, Director, Clinical Services for Blood and Blood Products, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., N., D5–280, Seattle, WA 98109, USA

© 2000 ISHAGE

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‘space used for processing a live vaccine shall not be used for any other purpose during the processing period for that vaccine . . . Live vaccine processing areas shall be isolated from and independent of any space used for any other purpose by being either in a separate building . . .’ [2]. Explicit advice about facility design is found in a guidance document prepared to assist in the preparation of an Investigational New Drug (IND) application for the manufacturing of somatic cell therapy products in which the FDA advises that, ‘For each manufacturing location, a floor diagram should be included that indicates the general facilities layout. This diagram need not be a detailed . . . blueprint, but rather a simple drawing that depicts the relationship of the subject manufacturing areas, suites, or rooms to one another, and should indicate other uses made of adjacent areas that are not the subject of the application. This diagram should be sufficiently clear that the reviewer may visualize the flow of production of the biological substance and would be able to identify areas or room ‘proximities’ that may be of concern . . .’ [3] These contiguties are important in determining the risk of cross-contamination including contamination from activities being conducted by others not a part of the facility. Even the placement and use of equipment comes under scrutiny. In the same guidance document, FDA advises, ‘Indication should also be given as to which additional products may share product contact equip-

ment with the product in question . . .’ [4]. Also part of the facility design will be the development of work instructions standard operating procedures (SOPs) for the cleaning of the facility and the disposal of waste. However, the facility is not the sole component of cGMP and the term cGMP encompasses much else that is important in the manufacturing of drugs and biologicals (Table 1). Contaminants may enter through other mechanisms. For example, in regards to the risk posed by employees of the facility, the cGMP for drugs requires that: ‘Any person shown at anytime (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components. . . . All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products.’ [5] FDA also requires that employees involved with live virus production cannot enter the virus production facility after having worked with other infectious agents in any other laboratory during the same working day [6]. Obviously, FDA expects that employees will shower and change clothes before returning to work although FDA appropriately avoids writing a regulation that, worded in this manner, would be difficult to enforce. Furthermore, contaminants may enter the manufacturing pathway through raw materials, reagents, and

Table 1. Elements of cGMP and ISO 9001 Quality System cGMP for finished pharmaceuticals (21 CFR 211)

Elements of the ISO 9001quality system

A. B. C. D. E. F. G. H. I. J. K.

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10

General provisions Organization and personnel Buildings and facilities Equipment Control of components Production and process controls Packaging and label controls Holding and distribution Laboratory controls Records and reports Returned and salvaged product

Management Quality system Contract review Design review Document control Purchasing Customer product Product identification Process control Equipment

4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20

Test equipment Inspection Nonconforming product Corrective action Handling, packaging Quality records Internal audits Training Servicing Statistics

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Current good manufacturing processes

supplies that are used in the production of a drug or biological. This requires oversight over materials and supplies be implemented by the processing laboratory. However, control over the materials used in manufacturing may not mean that the sterility and cleanliness of every supply used be proven – it does require that the laboratory establish a method that will achieve this end. A close-working relationship with the suppliers of raw materials and reagents must be established if this is not to become an onerous task for the production facility. FDA requires that, ‘Representative samples of each shipment of each lot shall be collected for testing or examination. The . . . amount of material to be taken . . . shall be based upon appropriate criteria for component variability . . . [and] the past quality history of the supplier . . .’ [7]. Obviously, shopping for the least expensive supplies with frequent changes in suppliers is not appropriate for the maintenance of quality. Finally, cGMP requires control over the actual manufacturing steps, the criteria for release of the product, and records. Detailed work instructions will reduce the variability in products. The requirements for cGMP are the same in these regards as found in the standards of professional societies such as the Foundation for Accreditation of Hematopoietic Cell Therapy (FAHCT) or American Association of Blood Banks (AABB), and will be very familiar to cell processing facilities that are accredited by either of these organizations [8,9]. FDA requires that, ‘Written production and process control procedures shall be followed. . . and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.’ [10] In summary, the operator of a cell processing facility in compliance with all the cGMP requirements will have a manufacturing pathway with reduced risks of inadvertent contamination and lot-to-lot variability. But does compliance to cGMP guarantee a quality product?

cGMP vs ISO 9000 cGMP is a quality assurance program. Many of the concepts included in these regulations comprise the basics of other quality assurance programs such as that described in the ISO 9000 approach (Table 1) [11]. ISO 9000 is but one of many quality assurance programs that are being broadly adopted internationally for manufacturing of a widely disparate products. In fact, FDA has adopted the ISO approach in its regulations regarding the manufac-

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turing of devices and titles this section of the CFR ‘Quality System Regulation’ [12]. This title is in contrast to ‘Current Good Manufacturing Practice For Finished Pharmaceuticals’ [13] for the section that applies to the manufacturing of drugs. The differences between cGMP and ISO 9000 requirements may appear subtle but are, for the latter, additional requirements for the establishment of a quality plan that applies to all sections of the facility including administration, the need for constant quality improvement, and the need for statistically valid sampling. The pharmaceutical cGMP requirements simply require that, ‘There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components . . . .’ [14]. The device regulations reflecting the ISO 9000 approach require that, ‘Management with executive responsibility shall establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization’ [15]. Furthermore, ‘Each manufacturer shall establish procedures for quality audits and conduct such audits . . . .’ [16]. The intent of quality audits is to detect deficiencies in the manufacturing pathway and to correct these deficiencies. Thus, quality programs such as ISO 9000 should result in continual improvement of the product. Facilities that achieve ISO 9000 certification should also easily comply with cGMP requirements if the FDAmandated facility design requirements of cGMP are accepted as necessary for the manufacturing of a quality product

cGMP and cGTP cGMP for drugs and biological products are defined in the CFR. FDA will shortly propose regulations that will define current good tissue practices (cGTP) that will apply to minimally-manipulated cellular and tissuebased products [17]. cGTP will define the minimal requirements for the production of these products that are not covered by the more extensive cGMP requirements that FDA will enforce for somatic cell therapy products [18]. cGTP will probably encompass the collection and laboratory practice standards found in the standards published by professional organizations such as FAHCT and AABB. Because these minimally-manipulated components are at less risk of adulteration and contamination, cGTP will not be as extensive as cGMP.

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Requirements for cell processing facilities cGMP, or other quality-focussed programs such as ISO 9000, forms an ideal to which all HSC collection and processing facilities should strive. However, most facilities will lack the financial resources to achieve this ideal. The construction of a facility that meets cGMP requirements is expensive; the ongoing expense of maintaining the cGMP environment will be onerous to small facilities. Although FDA has published its opinion that the somatic cell therapy products must be manufactured in accordance with cGMP requirements [18], academic programs exploring novel HSC manipulations such as ex vivo expansion or genetic modification should first discuss with FDA the necessity of conducting this research in a cGMP environment. These research programs are usually small, involve limited numbers of patients, and not intended to develop a commercial product. A wellwritten IND application that describes the manufacturing pathway including systems to prevent and to detect the introduction of contaminants may be acceptable in the ‘continuum of regulation’ that is applied by FDA, even if the design of the facility and the manufacturing pathway would not be appropriate for the manufacturing of a finished commercial product. As a product is developed, however, FDA will consider the design of the manufacturing plant, the equipment used, and the manufacturing pathway to comprise various aspects of the product, and products used in phase III studied intended to obtain licensure must be manufactured using the same pathways that will be used for the final commercial product. Given that HSC components are easily transported, sharing of a facility must also be considered, if manufacturing of a particular component requires this level of production. FDA does not propose that manufacturing of minimallymanipulated cellular and tissue-based products be performed under cGMP conditions and, because of the greatly increased costs with minimal benefit to the patient, few, if any, facilities can be expected at this time to adopt cGMP for the production of these products. This is not to suggest that facilities producing minimally-manipulated HSC components should ignore the philosophy inherent to cGMP or ISO 9000. The

philosophy of these quality programs is important to all HSC collection and processing facilities. The standards published by professional societies already require attention to quality management. As facilities become accredited by the programs, they should move beyond these minimal standards, examining all aspects of their programs including the design of the facility, use of equipment, training of staff, and relationships with suppliers and customers.

Acknowledgments Supported in part by grants CA18029 and CA15704 from the National Cancer Institute, Bethesda, MD, USA.

References 1 21 CFR 600.11(e)(3), 1998. 2 21 CFR 600.11(e)(4), 1998. 3 Guidance for the submission of chemistry, manufacturing, and controls information and establishment description for autologous somatic cell therapy products. Food and Drug Administration. Docket 95N-0200. Part 2.B.2. 1997. 4 Guidance for the submission of chemistry, manufacturing, and controls information and establishment description for autologous somatic cell therapy products. Food and Drug Administration. Docket 95N-0200. Part 2.B.3.1997. 5 21 CFR 211.28(d), 1998. 6 21 CFR 600.10(c)(4), 1998. 7 21 CFR 211.84(b), 1998. 8 Standards for Hematopoietic Progenitor Cell Collection, Processing & Transplantation. First Edition. Foundation for the Accreditation of Hematopoietic Cell Therapy. Omaha, 1996. 9 Standards for Hematopoietic Progenitor Cells. American Association of Blood Banks. Bethesda, 1996. 10 21 CFR 211.100(b), 1998. 11 The ISO 9000 Handbook. RW Peach, ed. New York: McGraw Hill, 1997. 12 21 CFR 820, 1998. 13 21 CFR 211, 1998. 14 21 CFR 211.22(a), 1998. 15 21 CFR 820.20(a), 1998. 16 21 CFR 820.22, 1998. 17 A Proposed Approach to the Regulation of Cellular and TissueBased Products. 62 Federal Register 9721, 1997. 18 Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products. 58 Federal Register 53248, 1993.