remain solely with the quality department.

Transcription

1 Barbara W. Unger An effective, welldeveloped, and versatile preapproval inspection model focuses management and inspectors on conclusions, minimizes process reinvention, and tracks inspection readiness, especially when you are using a contract manufacturer. 14 BioPharm FEBRUARY 2002 The most visible corporate focus in the development of new pharmaceutical chemical entities or biological products is generally on conduct of clinical trials and preparation of registration applications. But compliance inspection of the company s manufacturing site is equally necessary to product approval and commercialization. Often, preapproval inspection (PAI) activity begins late in the timeline and allows little or no opportunity to correct deficiencies. Added to that, each functional area maintains a list of activities to complete before a PAI, but those multiple plans must be coordinated to prevent duplication of effort, lack of harmonization among documents, and items falling through the cracks because each group assumes that another is taking care of that one. Using contract manufacturers increases the complexity of preparing for a PAI because it requires coordinating staff and information at two or more companies with different corporate cultures, inspection histories, and inspection experiences. Developing a model for thoughtful, planned preparation of inspection activities can provide common objectives for identifying and tracking strengths and deficiencies early and so allow for corrections or refinements. BUILDING A PAI MODEL The design of a PAI-preparation model will vary based on the organizational structure and operational specifics of each company. But all models should be well defined and easy to use. Implementing an integrated PAI preparation model ensures that the entire project team is responsible and accountable for inspection readiness and compliance rather than having responsibility remain solely with the quality department. One approach to PAI model development is constructing and collecting tools designed to identify action plans, track progress, capture issues, report performance, manage documents, and maintain critical information. One deliverable then produced is a threering binder containing all the information necessary to support areas that may be inspected by regulatory agencies. However, that information is not for submission to regulatory authorities, but is instead a resource book for corporate staff supporting the inspection. Cataloging that information in one place enables rapid retrieval and management of documents and data requested by regulatory inspectors and identifies appropriate personnel with specific technical expertise. Another deliverable generated by this model is a standardized graphic representation of compliance status that can be used to update the organization. Such a tool is most crucial for companies with multiple products on the market or in PAI preparation. IDENTIFYING THE TOOLS Preparing and using a set of common, welldefined tools ensures that training is institutionalized and that PAI readiness activities are proactive rather than reactive. Such tools ensure that all teams within the company develop a common understanding of the current regulatory compliance environment, of recent inspection focus within the industry, and of their own companyspecific inspection experiences. The tools can

2 minimize situations in which each project team rediscovers and applies its own version of a process. It may be advantageous (depending on the structure and organization of the company) to align the appearance and structure of tools used for PAI-readiness preparation with those that may be used to prepare the chemistry, manufacturing, and controls (CMC) section of regulatory submissions. That link between CMC regulatory and quality activities simplifies the work assignments for those involved in document preparation and collection to support both regulatory and quality activities. Three basic tools can reasonably be incorporated into a model for PAI preparation: a planning matrix, an instruction manual, and compliance status tracking forms. A planning matrix is a to do list of activities, collected as a series of spreadsheets, which identify high-level inspection readiness categories for those areas that regulatory agencies will review during inspection. Agencies inspect manufacturers to ensure that a plant site is capable, that equipment is properly installed and qualified, that employees are trained, and that data in each application are authentic. Additionally, data supporting scale-up and site changes between production of the product used in pivotal clinical studies and commercial production are generally evaluated to ensure that product is comparable or bioequivalent. The identification of high-level inspection categories (as shown in Table 1) can be followed by a subset of project- and product-specific items, assignment of accountability, and projected due dates, with brief narrative comments in support of each line item (Tables 2 and 3). The project team can expand Tables 2 and 3 to meet the specific needs of the projects within those areas. For example, the regulatory documents category, listed as section 2 of Table 1, can be divided into multiple subcategories (Table 2) and include copies of submissions to regulatory agencies, development history reports, primary and supporting stability data, key lot identification, validation summaries, and site-specific documentation such as drug master files (DMFs). For items provided to regulators, such as primary and supporting stability data, identifying the pages in a submission where that information can be found is preferable to duplicating those pages for a three-ring binder of summary information. When a cooperative manufacturing option is used, preparation for inspection should take into account the nature of the business alliance and written contractual agreements. Both CBER and the European Union expect written agreements to specify roles and responsibilities of each partner or contractor. A quality agreement between partners can form the basis for identifying highlevel roles and responsibilities relative to preapproval inspection. A shared planning matrix gives partners a common set of detailed action items and identifies PAI responsibilities that are consistent with contractual agreements. The planning matrix should be reviewed routinely by a team representing the functional areas participating in an inspection. Such meetings allow the team to track activities and to identify the need for additional resources in specific areas. The planning matrix can be modified to indicate whether items are completed by the projected due date. The due date cell within the tables can be shaded or colored, with green (for example) indicating an item that is on track for completion by the projected due date, blue indicating a completed project, and red indicating the need for a revised due date. The instruction manual. The line items in Tables 2 and 3 are quite general. An instruction manual can help a project team identify and add project-specific activities. An instruction manual explains the general line items and suggests functional areas or specific individuals accountable for providing that information. The instruction manual identifies information, where possible, that is presented in the registration application and so provides a direct link between quality and CMC regulatory activities, minimizing duplication of effort. For example, an instruction manual might indicate that an analytical scientist should be responsible for the stability data line item identified Table 2. Section 2, available regulatory documents Table 1. High-level categories for preapproval inspection planning matrix Section Available Regulatory Documents Who Due Date Status A. Regulatory submissions and communication Cindy 4/15/02 B. Development history reports Cindy 4/12/02 C. Stability data Mike 3/15/02 D. Key clinical trial lots Tom 11/03/01 E. Key manufacturing lots Mary 1/15/02 revised to 2/02/02 F. Validation summaries Cindy 6/2004 G. Site-specific documentation Cindy 6/2004 Colors in the Status column are part of the tracking process with green indicating a project that is on track for completion by the projected due date, blue indicating the item is completed, and red indicating the need for a revised due date. When a due date is missed, the box does not become green again. Title 1 State of CGMP compliance 2 Available regulatory documents 3 Key batch records 4 Analytical methods history 5 Analytical methods transfer 6 Analytical data 7 Preparation of launch materials 8 Other project-specific issues 9 PAI logistics and execution BioPharm FEBRUARY

3 Table 3. Section 3, key batch records Key Batch Records Who Due Date Status A. Conformance to regulatory requirements, clinical trial lots Bob 3/15/02 B. Conformance to regulatory requirements, commercial lots Mary 11/29/01 revised to 12/15/02 C. Identification of clinical trial lots Tom 11/03/01 D. Samples Sue 3/20/02 Colors in the Status column are part of the tracking process with green indicating a project that is on track for completion by the projected due date, blue indicating the item is completed, and red indicating the need for a revised due date. When a due date is missed, the box does not become green again. Example from an Instruction Manual 3.D. Samples Purpose: Samples are needed for testing by FDA labs and for in-house retention. Responsibility: CMC team Deliverable content: Identify the location of the following samples: 1) methods validation samples, 2) house retention samples, and 3) samples for EU countries. Samples provided to FDA for methods validation cannot exceed the expiry dating. The method validation samples are provided for the United States only. 1. The samples required for methods validation are described in the FDA Guideline for Submitting Samples and Analytical Data for Methods Validation (February 1987) in support of 21 CFR (e). This includes four representative samples, each in sufficient quantity to perform three (3) times each test that is described in the application for: Drug product proposed for marketing Drug substance used to make the drug product as provided above Reference standards (those from official compendia need not be submitted) Samples of finished market package if requested by FDA 2. The quantities of in-house retention samples are specified in the corporate GMP (SOP procedure number ). Samples should be retained consistent with the current version of this procedure. 3. For the purposes of implementing Article 4 of Directive 75/319/EEC, samples of the (nonpharmacopoeial) active substances, and of the finished medicinal product must be supplied at the same time as the submission of the dossier as a matter of course to the competent authorities in Italy (see table in actual publication), Luxembourg, Spain, Sweden, and Portugal in accordance with the requirements set out in this table in section 5.2 for national and mutual recognition submissions. In other cases, samples should be provided at the request of the competent authorities. 16 BioPharm FEBRUARY 2002 in the planning matrix as item C in Table 2. The instruction manual may further direct the reader to the section of the registration application that provides primary and supporting stability data. Although the instruction manual can suggest functional areas responsible for specific tasks, the project team should assign accountability for each line item to specific people and incorporate those names into the planning matrix. Assigning specific names to specific tasks ensures ownership of a responsibility and encourages timely completion of assignments. An instruction manual can also identify the nature and scope of the deliverable for each line item. For example, the manual can clarify whether the deliverable should be a reference to pages within the registration application, identification and location of specific development history reports, or specific printouts from the corporate analytical database. This provides consistency across project teams and clearly identifies the expectations for deliverables. An instruction manual should also list references to regulations, regulatory agency guidance, corporate policy, guidelines, and SOPs for each line item within the planning matrix. Some line items may have no references, whereas references for others may be quite extensive. References help team members understand the basis behind a request for information. For example, item D in Table 3 lists samples, and the Sample Instruction Manual sidebar details information that might be included in the instruction manual for that line item. The instruction manual explains that this line item includes samples required for methods validation as described in 21 CFR (e), in-house retention samples, and samples of nonpharmacopoeial active substances in support of Article 4 of Directive 75/319/EEC that are submitted to some regulatory authorities. In addition, the instruction manual may identify the corporate SOP that describes the retention of house samples. The choice of references to be included should reflect the company s registration strategy (that is, global or United States only) and its corporate organization. Compliance status tracking form. Another useful tool in preparing for a PAI is a tracking form that provides a standardized graphic representation of compliance status for major inspection categories. A standardized format is particularly useful for presentations to management because it is consistent across different projects and provides summary conclusions without unnecessary detail. Table 4 shows a sample status tracking form. The form can be keyed alphanumerically or color coded. The example shown uses U to indicate an unacceptable status, meaning that the item has serious deficiencies; NI to indicate a category in need of improvement, that is, it has less serious deficiencies; and S to indicate satisfactory compliance status. The compliance status of an item can be established through audits performed by the quality department. Follow-up status should be reviewed at predetermined intervals.

4 Table 4. Readiness status tracking form using some major activities for drug substance purification as an example Status a Topic Jan Feb Mar Apr May Jun Equipment IQ and OQ b NI S S S S S HVAC systems NI NI NI S S S Water systems NI S S S S S Computer systems U NI NI NI S S Procedures U U NI NI S S Change control NI NI NI S S S Cleaning U U U NI NI S Training U NI S S S S Process validation NI NI NI S S S a S = satisfactory compliance status; NI = compliance item needs improvement; and U = compliance status is unsatisfactory b IQ = Installation qualification and OQ = operational qualification 18 BioPharm FEBRUARY 2002 IMPLEMENTING THE TOOLS As with any tool, those suggested here are used most effectively by a knowledgeable, coordinated team. The project team develops action plans to prioritize and address specific deficiencies identified during audits. The penultimate test of a PAI model s usefulness can be measured during a mock PAI, frequently performed by experts from outside the company. Remember that tools are not an end result but rather a standardized means for achieving common goals across and between companies. Training and coordination. A successful PAI model ensures that all project team members understand the process, their responsibilities, and the corporate and regulatory expectations. To achieve that, the quality department representative on the project team can train the team on the process. That allows team members to understand expectations and coordinate the required activities with their other responsibilities. For example, team members who know that their functional units should expect quality department audits as part of the process can accommodate that within their timelines. A member of the quality department may be assigned to coordinate overall preparation for a PAI, making that member the owner of the planning matrix and the status tracking forms. That member can also be responsible to the team for guidance regarding document identification, preparation, and auditing. Baseline quality audits. Key to PAI preparation is determining the compliance status of the major inspection categories presented in the planning matrix. When the project team has completed the planning matrix, the quality department (or another unit depending on corporate structure) can be made responsible for establishing compliance status. Compliance status evaluation should be an ongoing process, rather than an activity undertaken for the first time just before a PAI. A first step in planning focused audits is to identify what may best be termed auditable units. Auditable units are those related activities that can be audited simultaneously by a small audit team. For example, a cell bank preparation audit can include evaluation of the host cell line history, preparation of the expression construct and the history of the construct s genetic components, selection of the production cell line, and evaluation of the cell banking process. More detailed audits of those tasks might include evaluating personnel training, identifying existence of and compliance with appropriate SOPs, evaluating record documentation, and evaluating the facility relative to containment and prevention of cross contamination. Identifying and grouping auditable units allows the quality department to develop an orderly plan and timeline for its activities and also encourages status capture of tasks on the tracking sheets. When audits have been completed, an initial assessment (such as U, NI, or S ) is applied relative to the line items on the tracking sheets. Functional areas, with assistance from local quality department staff, can monitor ongoing compliance status of major categories periodically. Action plans developed by those functional areas to address audit findings can be incorporated into the planning matrix, and progress toward resolution can be monitored routinely. Mock PAI. Conducting a mock PAI is strongly recommended: It is essentially a dress rehearsal for an inspection and can help participants identify areas in which additional coordination, training, and data are necessary. Using experts from outside the company to conduct the mock PAI can be useful. Before the mock PAI, the PAI model has dealt mainly with evaluation of systems and the identification and review of documents. A mock PAI is the time to test the integration of those efforts and the ability of staff and operators to confidently and concisely represent their activities consistent with the batch records, SOPs, and the registration application. Ultimately, the PAI readiness plan is only that, a plan and a collection of tools with which to prepare for the inspection. The success of a PAI depends on the knowledge, confidence, and consistency of the individuals presenting the systems, facilities, and operations to the inspectors. Continued on page 71

5 LITERATURE LITERATURE LITERATURE LITERATURE LITERATURE LITERATURE LITERATURE LITERATURE LITERATURE Depth filter A brochure from SeitzSchenk Filtersystems describes the SUPRAdisc II, designed for higher flows and increased contaminant loading in critical applications. Design features, applications, and benefits are explained with lists and illustrations. SeitzSchenk Filtersystems North America, Timonium, MD. Info #137 Chromatographic resins TOSOH Biosep is a virtual manufacturing partner with many pharmaceutical and biotechnology companies. The company s TSK- GEL, Toyopearl, and Amberchrom chromatographic resins are elements in the analysis, isolation, and purification of biomolecules. A company brochure describes services offered and includes more information about the company. TOSOH Biosep, Montgomeryville, PA. Methods development A brochure from Waters Corporation describes an eightstep approach for rapidly developing stability-indicating methods. The kit described by the brochure includes four columns and a how-to handbook. The approach is based on International Conference on Harmonisation guidelines for registering pharmaceuticals for human use. Waters Corporation, Milford, MA. Enzymes The Worthington catalog features research products, cell biology and tissue dissociation kits, and application notes. The company accommodates bulk purchasing and provides standing-order discounts and technical assistance by phone or Internet. All animal products are collected in USDAapproved facilities. Worthington Biochemical Corporation, Lakewood, NJ. BP Info #138 Info #139 Info #140 PAI Preparation continued from page 18 BEING PREPARED Developing and implementing a successful model for PAI preparation unifies the company s approach and focuses on the links between quality activities and CMC regulatory activities. An effective model provides a common set of tools to different functional areas and a basic, flexible framework to respond to project needs and cooperative manufacturing arrangements. An optimal model institutionalizes training and sharing among project teams and minimizes the instances in which individual teams rediscover expectations and reinvent processes. When contract manufacturers are used, a well-defined model ensures that multiple corporate entities work from a common set of expectations and shared standards to track inspection readiness. The model and the process are versatile and can be used for drugs, biologics, and combination products to identify inspection issues, establish accountability, and track status. The instruction manual can be updated easily to reflect changes in regulations, guidelines, corporate experience, or the regulatory compliance environment and provides the company with a current, consistent set of expectations regarding PAIs. The status tracking forms are valuable for management presentations because they provide a common reporting graphic for a variety of projects and focus attention on conclusions. PAI readiness models can be tested by conducting mock PAIs that illustrate the company s ability to accurately and concisely represent its product and facility to inspectors. ACKNOWLEDGMENT The author would like to acknowledge the valuable critical review of the paper by Glenn E. Wright, director, regulatory affairs, Eli Lilly and Company. FOR FURTHER READING Center for Drug Evaluation and Research, Guideline for Submitting Samples and Analytical Data for Methods Validation (FDA, Rockville, MD, February 1987). Available at guidance/ameth.htm. Code of Federal Regulations, Food and Drugs, Content and Format of an Application, Title 21 Part (e) (U.S. Printing Office, Washington, DC, revised April 2000). Enterprise Directorate General, Notice to Applicants: General Information, Pharmaceutical Legislation: Procedures for Marketing Authorisation, Ch. 7, Vol. 2A, ENTR/F/2/LVD(2001) (European Commission, Brussels, July 2001). BP Barbara W. Unger is a regulatory consultant for Don Hill Associates, Inc., PO Box 6215, Silver Spring, MD 20916, , fax , bwunger@midlink.com. BioPharm FEBRUARY