Preparing for team biologics inspections

Central to preparing for Team Biologics inspections is knowing what to expect and how those inspections will differ from what has gone before.

During the past year FDA implemented a new program called Team Biologics for inspecting the biologics industry (1). The program will have a significant impact on companies covered under the initiative because FDA will be using techniques and approaches unlike those previously used by Center for Biologics Evaluation and Research (CBER) personnel. Under Team Biologics, the lead responsibility for biennial inspections has been transferred from CBER to the Office of Regional Affairs (ORA). This article provides some insight into the changes that will result from implementation of Team Biologics and offers information for predicting FDA actions in the biologic industry as a whole. Described are some techniques that may be used by companies to systematically verify readiness.

Prudent managers will provide training to ensure that all employees know what to expect when their company undergoes its first inspection under Team Biologics. Responsible staff should fully anticipate the activities of FDA and take the necessary steps to prepare for an inspection. In contrast, some companies will not recognize the trends and are likely to be caught unaware, suffering severe consequences if found to be noncompliant with GMPs. Unless companies anticipate the new inspection approaches and take certain steps, they may well experience an unfavorable outcome from their first Team Biologics inspections. In fact, certain segments of the biologics industry have already been inspected, and some companies have experienced adverse consequences including lengthy FDA 483s, warning letters, and consent decrees.

PreapprovalInspections

The recent number of biologics companies that Team Biologics has found to be in noncompliance and the severity of the Team's findings at certain facilities are unprecedented for the biologics industry. But that is similar to what has happened in other segments of the pharmaceutical industry. Notable parallels exist between recent findings of Team Biologics and problems that occurred in other segments of the pharmaceutical industry over the past two decades. For example, in the 1970s FDA initiated systematic inspection coverage of the large-volume parenteral (LVP) industry following a number of septicemia outbreaks in the United States and Europe. FDA dispatched teams of investigators, microbiologists, and engineers to focus on conditions and practices related to sterility assurance. FDA teams found virtually the entire industry to be noncompliant with CGMPs. Following those inspections, numerous plants were shut down for renovations, and shipments of products were suspended. Product recalls numbered in the hundreds, FDA initiated rigorous regulatory sanctions that led to the requirements for sterilization process validation, and in 1978 the GMP regulations were revised (2,3).

Industry-widenoncompliance During the 1970s and 1980s, several FDA initiatives sent teams of specialists out to perform intensified inspections across entire segments of several industries. Those teams found widespread compliance problems. During those first rounds of intensified inspections, FDA found what it considered to be serious noncompliance across entire segments of the health industry. Industry surveys detected widespread problems in facilities that previously were considered by the industry to be in a reasonable state of compliance. For the medical device, lowacid canned food, blood bank, and computer software industries, FDA initiated compliance sanctions or issued new regulations, guidelines, or guidance documents.

Preapproval inspection (PAl) program launched. In the early 1990s, FDA initiated the PAI program in response to an investigation by Congressman John Dingell's (Democrat, Michigan) House Oversight and Investigations Subcommittee of the Committee on Energy and Commerce (4). FDA assembled teams of investigators, analysts, and other specialists to survey record-keeping practices and GMP compliance in the generic drug industry. (Another outcome of the PAI program has been the routine use of teams made up of FDA investigators and national experts, analysts, and engineers.) Those inspections detected serious GMP violations and application integrity discrepancies, including fraud, in many companies. FDA initiated various regulatory sanctions including criminal prosecutions, debarments under section 306 of the Food, Drug and Cosmetic (FD&C) Act, warning letters, and withholding application approvals. Because of the high incidence of compliance problems found at manufacturers of generic and nongeneric drugs, FDA continued intensified coverage under the PAI program for almost a decade because the inspections detected a relatively high rate of problems with application integrity and GMP compliance.

CDER currently recommends

withholding approval at about 20 percent of sites inspected under the PAI program. According to Stephanie Gray, director of FDA's Office of Compliance, during fiscal year 1995, 42 percent of the international pharmaceutical facilities FDA inspected under the PAI program resulted in recommendations to withhold application approval (5). Unquestionably, the PAI initiative has improved industry awareness of FDA requirements, and many companies have made significant improvements as a direct result of that program.

0IG questions FDA. In June 1997 the Office of Inspector General (OIG) issued a report that described its investigation of how FDA handled a number of incidents involving plasma fractionation products (6,7). The OIG report raised questions about how effectively CBER handled certain situations involving contaminated biologicals and/or recalls, and it included FDA's comments about information contained in the draft report. Because FDA actions were scrutinized by OIG, it is not surprising that FDA gave this matter priority attention. Team Biologics is FDA's attempt to achieve corrective action to the issues that were raised in the OIG report. FDA management is well aware that its actions are likely to be under further review by OIG or other special interest or oversight groups. Therefore, the agency has already initiated actions to ensure uniformity of inspections and enforcement between biologics and drug products.

A cadre of experts. One outcome of the OIG report has been a significant change in the way inspections are conducted. The transfer of lead responsibilities for biennial biologics inspections from CBER to ORA ensures the same approach for all drug products. The new partnership between CBER and ORA is intended to ensure more effective and efficient regulation of biological products by using a cadre of specialized staff who will devote their attention to biologicals (see "A Cadre of Experts" box).

learn Biologics: A New Approach As FDA rolls out its Team Biologics initiative, many biologics manufacturers will see differences between the Team Biologics approach and those approaches formerly used by CBER. Inspections may be longer in duration, they may focus more intently on documentation issues, and more rigorous sanctions may be enforced when deviations are encountered.

For many years, inspection approaches and regulatory enforcement by CBER and CDER differed notably. Before Team Biologics, CBER staff from its headquarters in Rockville, MD, performed inspections of biological products, and investigators from ORA field offices performed pharmaceutical inspections. Historically, personnel from CBER and ORA used separate inspection programs and followed different approaches. The scope and content of their inspections were not the same. Until recently, CBER inspections were generally shorter in duration and frequently focused primarily on scientific or technical issues dealing with establishment license applications (ELAs) or product license applications (PLAs).

In contrast, ORA field investigators conducted CDER inspection programs, and inspections were usually of longer duration. ORA field investigators typically gave greater attention to GMP compliance and documentation issues. Although statistics comparing enforcement rates between CBER and CDER are not readily available, there has been a long-standing perception that enforcement sanctions by CBER were less aggressive than CDER and ORA. With the implementation of Team Biologics, manufacturers of biological products who are not in substantial compliance with CGMPs are likely to face more rigorous enforcement sanctions -- sanctions that FDA considers to be consistent with actions that have been taken for drug products than in previous years.

Prudent companies will anticipate those changes in FDA priorities and take proactive steps to prepare for Team Biologics inspections. One of the more important steps is to ensure that personnel are well aware of the changes and know what to expect before FDA arrives so they can ensure GMP compliance for the quality systems that are most likely to be given priority attention by FDA (see the "Inspection Priorities" box).

Emphasis on field operations. Several factors contribute to the differences between CBER and CDER. For example, for many years field investigators were generally discouraged (or prevented) from inspecting facilities that manufactured biologics. The biologics portion of a facility was often "off limits" to ORA field investigators. Past CDER inspections were performed by staff from the headquarters unit with minimal interaction between CBER and the field offices. Team Biologics inspections will be performed by teams with representatives from both units (see "A Cadre of Experts" box). Previously, it was common for CBER personnel to perform inspections at a facility located in one of FDA's geographical regions without notifying the local district or providing it with copies of their inspection reports. In contrast, Team Biologics inspections will be carefully coordinated, and reports will be written jointly. Another notable change is the transfer of lead responsibility to ORA, which is likely to result in a significant increase in the frequency of enforcement actions. As Team Biologics inspections give greater attention to GMP compliance and documentation issues, FDA expects to find a disproportionate number of biologics manufacturers in noncompliance, as when FDA began its intense coverage under the PAI program in the early 1990s.

As FDA intensifies its scrutiny of the biologics industry and begins to find evidence of noncompliance, personnel in affected companies may believe that FDA is being unfair or is changing the rules. Such persons may feel that FDA is now applying a different standard and that they have not been given sufficient notice or opportunity to come into compliance before FDA initiates legal proceedings. ORA field staff are likely to take an alternate view that enforcement actions under the Team Biologics initiative are consistent and uniform with the standards that have been applied to the pharmaceutical industry for a number of years.

Now Team Biologics trans. Preparing for Team Biologics starts with understanding how the team trains. Preinspection training at your company should describe the new paradigm FDA will follow to prepare for Team Biologics inspections because this is unlike techniques that were previously followed by CBER. Before a Team Biologics inspection, the team will review relevant central files to determine the compliance history of the facility to be inspected. That review may include obtaining copies of relevant CBER inspection reports for biologic products and copies of pharmaceutical inspection reports from the local district office or CBER headquarters unit. Team members may meet for preinspection briefings or coordinate their efforts by phone, fax, or email as appropriate.

In some cases, FDA inspection teams may be briefed for two to three days before an inspection when they have an opportunity to meet directly with the staff from various headquarters units and to review original copies of ELAs, PLAs, biologics license applications (BLAs), or drug master files (DMFs). During such meetings Team Biologics members will discuss strategies with chemists or microbiologists from field laboratories and/or CBER staff who have reviewed applications. If a company has a history of compliance problems, Team Biologics members will consult with district or headquarters compliance staff to determine the appropriate follow-up to previous inspection findings. The team will review previous inspections for evidence of significant problems and will use that information to prepare an inspection strategy.

In addition, the team will review applicable correspondence with special attention to corrective actions that may have been promised or responses that reflect incomplete or inappropriate actions from problems that may have been detected previously. Each team member will provide input about areas of concern, priority issues that should be addressed, or any other discussion as appropriate.

Inspection Techniques

Team Biologics inspections will vary with each of the product areas identified in the program and the experience level of the team members. Team Biologics inspections will use the same inspection techniques and will focus on the same type of quality systems commonly covered for medical devices and drug products. When GMP deviations or application integrity deficiencies are encountered, FDA enforcement practices will be the same as those that ORA field offices have used for many years. For example, an ORA compliance officer team member will be responsible for immediately notifying the CBER Office, of Compliance and the ORA Office of Enforcement, and CBER will jointly provide administrative support for civil and/or criminal actions.

Enforcement act^OO The Core Team will develop its own recommendations about the actions deemed necessary to resolve compliance issues. Team Biologics is intended to facilitate enforcement sanctions by allowing the development of direct reference authority such as those that have been in place for many years in FDA's Compliance Policy Guides (CPGs). ORA field offices have for many years been given direct reference seizure authority for CDER products under certain situations as described in the CPGs. For example, CPG 7132a.03 authorizes district offices to submit seizure recommendations, charging adulteration under section 501(b), directly to the Office of Enforcement without CDER review under certain specified conditions (9).

Under Team Biologics, team members have been given greater latitude to develop enforcement actions and coordinate those actions with the appropriate compliance staff in ORA and CBER. The net effect of that change will likely be more frequent and more swift enforcement actions than occurred previously for biologics. For example, warning letters and relatively routine compliance actions will be forwarded to the CBER Office of Compliance to ensure expedited review and consistency, and more complex and/or serious regulatory actions will be sent to ORA's Office of Enforcement for review on an ad hoc basis. Before an inspection is completed, the inspection team will develop an enforcement strategy on an ad hoc basis in cooperation with the appropriate offices within CDER, CBER, and ORA.

Preinspection Training

To ensure a successful inspection under Team Biologics, companies should anticipate the need for considerable preparation and attention to a number of details. The odds of a successful inspection under Team Biologics will be determined by the level of preparation by key staff and by the overall level of compliance in the areas inspected by FDA. Personnel at biologics companies will be at a disadvantage if they do not fully understand the requirements, expectations, and inspection techniques that ORA field investigators routinely use. Problems may develop when employees do not know what to expect or when they do not effectively anticipate the needs of the FDA team. Prudent companies will train their staffs to ensure that everyone understands what to expect and to confirm that key personnel initiate the actions necessary to verify that each facility is in substantial compliance with GMPs and is following the commitments made in ELAs, PLAs, and BLAs.

Companies should design training programs based on their own experiences with FDA inspections under ORA and CDER programs. Companies that have little or no prior experience with ORA field investigators should prioritize training for their key staff members. Unless key personnel fully appreciate what to expect, companies may not take the actions necessary to ensure compliance. And if FDA detects substantial noncompliance, the company may suffer adverse consequences.

Senior management (directors and vice presidents) and key personnel (managers, supervisors, and technical staff) in each department (production, laboratories, QA/QC, engineering, development, and so on) should participate in pre-inspection training. Training sessions should describe the Team Biologics initiative and identify the respective roles and responsibilities of key personnel and the actions needed to prepare for such inspections. Training should include effective techniques for dealing with FDA investigators and the expected role of each participant during Team Biologics inspections. Upon completion of the training, key employees should clearly understand what is expected of them before, during, and after a Team Biologics inspection. Not only will they know what duties are expected within their respective work groups to prepare for the inspections, they will also be responsible for ensuring that their direct reports understand what to expect and how to act during a Team Biologics inspection.

Anticipating inspection Priorities

Team Biologics inspections will normally focus on two main issues: verifying the integrity of information supporting applications (ELAs, PLAs, and BLAs) filed with FDA, and determining conformance with GMPs at the facilities used for manufacturing, processing, packing, and holding a biological product. FDA inspection techniques and priorities are well known for most conventional manufacturing processes, and the same basic approaches will be applied to biologics. FDA techniques vary for each dosage form (sterile injections, oral tablets or capsules, topicals, transdermals, and so on) and will address key manufacturing processes (powder blending, granulation, and compression; liquid ultrafiltration; gel chromatography purification; aseptic filling; and terminal sterilization). For a given dosage form or manufacturing process, FDA can be expected to apply the same basic requirements to drug products and biologicals (unless the biological product has unique attributes or requirements that will be taken into account as appropriate). The following are a few examples of the priorities likely to emerge as FDA rolls out the Team Biologics initiative across the biologics industry (see also the "Inspection Priorities" box).

Application integrity. Companies should anticipate that Team Biologic team members will have had substantial experience under the ORA-DER PAI program and may give considerable attention to application integrity issues (4). Team Biologics inspections will provide an inspection focus unlike previous CBER inspections, and biologics manufacturers should anticipate that FDA may systematically compare application commitments against current practices. Biologic manufacturers should expect rigorous attention by Team Biologics if application integrity issues are suspected, and severe consequences will result if FDA obtains documented evidence of application integrity problems. The Team Biologics inspection team may spend considerable time and efforts reviewing documents that have been created during the development project (or changes made since application approval by FDA) and will compare that information with application commitments contained in ELAs, PLAs, and BLAs.

Companies that submitted ELAs or PLAs many years ago should verify that current conditions and practices in each facility are consistent with commitments contained in approved applications. FDA will be alert for changes to equipment, manufacturing processes, specifications, regulatory analytical methods, and other areas where companies may have made changes without obtaining approvals. FDA will review change control documentation and will compare information contained in approved applications to determine if there are discrepancies. If significant discrepancies are detected, FDA will likely expect companies to recall affected products (or FDA may initiate seizure actions). If FDA detects serious application integrity discrepancies, the preferred action will be to invoke the Application Integrity Policy (AIP), formerly called the "fraud policy" (10,11).

AIP is a program that FDA uses to deal with instances where it has reason to believe that persons have committed wrongful acts that raise questions about the reliability of data contained in filed applications. The consequences of being under the AIP are extreme, and while validity assessments are in progress, FDA will generally suspend review of pending applications until integrity questions have been resolved. When FDA investigations reveal substantial questions about the reliability of data and information contained in an application, several potential sanctions may be invoked. See the "FDA Sanctions" box for a list of those sanctions.

Prudent biologics manufacturers will ensure that key staff are fully aware of any application integrity problems that have been detected in other segments of the drug and medical device industry during recent years and will take proactive steps to verify the integrity of their applications and supporting documentation. Companies that do not ensure application integrity will face serious consequences if FDA finds evidence of integrity problems during Team Biologics inspections. FDA staff will obtain copies of current filings, including supplements and amendments, and will examine original supporting documentation at the manufacturing or testing facility to verify conformance with commitments.

During the first few years of intensified coverage under the PAI program, FDA encountered a relatively high percentage of companies that were not in conformance with their regulatory commitments. Various FDA enforcement reports and trade publications in recent years have shown that FDA continues to find application integrity problems in a number of companies that manufacture finished pharmaceuticals, active pharmaceutical ingredients, and medical devices (13-19). For example, in fiscal year 1995 FDA investigated more than 38 medical device applications under the AIP (19). Daniel Michels, director of ORA's Office of Enforcement, reported that 74 arrests were made in fiscal year 1996 by FDA's Office of Criminal Investigations (OCI), the unit responsible for investigating criminal actions by industry or FDA personnel (20).

Standard operating procedures (SOPs). Many biologics manufacturers have not established written SOPs for verifying the accuracy of documents contained in ELAs and PLAs before filing them with FDA and may not have verified their accuracy at time of original filing or postfiling. Companies should anticipate that Team Biologics may perform application integrity audits, and before FDA inspections, responsible personnel should become fully aware of the company's documentation systems (locate the records supporting any application filings). Personnel should review procedures that describe the schemes for identifying records, verify the adequacy of the document filing and retention practices, and identify the storage locations of documents cited in applications (such as those in support of batch production and control activities).

When it is practical, key personnel should prepare lists that identify available supporting records and the specific location of the records if they need to be retrieved during an inspection. For multinational companies that work at several sites or for companies that use contract services, it is important to ensure that records and data are retained at the locations where the activities were actually performed.

FDA expects that laboratory data (raw data and original records) will be retained at the site where testing is performed and that batch production records will be kept at the plant where batches were formulated. FDA does not want companies to move records from their original storage locations for the purpose of inspection. As necessary, inspection teams will go to the facilities where the various activities were performed to inspect the raw data and original records. For example, FDA would review data for testing performed by a contract laboratory at the contractor's facility. If necessary, inspection teams may visit remote sites to audit data and practices.

To the extent possible, companies should review current applications for products that are likely to be inspected by FDA under Team Biologics to ensure application integrity. If applications were not systematically verified for accuracy before filing, then it is advisable to perform such verifications before the inspectors arrive. If practical, companies should perform an internal audit of each ELA, PLA, and BLA to ensure the filings are factually correct and contain complete and up-to-date information (the information should reflect current conditions, practices, specifications, and test methods). Audits should verify that appropriate amendments or supplements have been filed to cover any changes made since the original submissions. If discrepancies are detected, the appropriate amendments and supplements should immediately be filed with the agency.

Mack FDA inspections. Application integrity audits systematically compare information that is contained in applications with raw data and original records. Such audits serve two important purposes. First, they allow a final opportunity for the company to independently verify that information in its applications is accurate and supported by raw data. Second, they provide plant personnel a chance to undergo a simulated FDA audit, providing valuable experience for those having to answer questions and locate supporting documentation. Audits also provide management with the opportunity to observe how well their key personnel deal with the pressures of an audit and to judge how effectively they communicate. Management may use this experience to decide the roles and responsibilities of key personnel during a Team Biologics inspection. In some cases it may be necessary to provide additional training or instruction on how to be more effective during audit situations.

Scale-up and postapproval changes (SOPAC). Since 1994 FDA has been actively developing SUPAC guidance documents for the pharmaceutical industry (21-24). Generally those documents do not directly apply to most biological products, but it is prudent that manufacturers of biological products understand the background and reasons that led to their development. For biological manufacturers who may have filed their ELAs or PLAs many years in the past, it is likely that conditions and practices used in production and control have been changed over the years. Team Biologics will likely focus on change control issues, and the team will be alert for changes that may be outside the application commitments.

Targeting Priority Systems

Team Biologics inspections will focus on certain quality systems to determine whether a facility is in substantial compliance with CGMPs per section 502(a)(1)(2) of the FD&C Act (25). Although each FDA investigator, chemist, and microbiologist may have a particular style, approach, or unique set of priorities, there will be a predictable similarity between inspections of drug and biological products. For example, Team Biologics inspection approaches and priorities will obviously vary by dosage form and method of manufacture. But there are a number of priority systems that can be expected to be covered during most inspections, and the approach for document review will follow the techniques that have been used for years by ORA field staff. For the same reasons described for application integrity audits, it is advisable to perform internal GMP audits before a Team Biologics inspection. Such audits may focus on product development, scale-up to fullsize production batches, qualification of equipment and utilities, validation of processes and laboratory methods, batch records and SOPs, and many other areas. Biologics manufacturers should identify a comprehensive list of systems most likely to be covered under Team Biologics and, before FDA arrives, take the necessary steps to ensure GMP compliance for each.

Laboratory controls. Expect most Team Biologics inspections to focus on laboratory controls (microbiological, chemical, physical, or other). Depending on the dosage form and product category, the inspection team will include an analyst and/or a microbiologist. Under the PAI program for a number of years laboratory controls were one of the most commonly cited deviations, and under Team Biologics companies should anticipate a similar focus. At each site, for example, FDA will examine the laboratory controls to ensure that instruments are calibrated at suitable intervals according to established written procedures.

Team Biologics will give special attention to determining the adequacy of documentation for results of analyses that are out of specification (OOS), including indepth review of investigation reports used to support decisions to release or reject batches with OOS results. FDA will look for instances in which batches with OOS results may have been released based on inappropriate decisions or retest results that were not supported by sound scientific rationale. FDA will review procedures used to maintain records for trending laboratory OOS results and test failures, their reasons, and corrective actions. FDA analysts can be expected to focus on methods validation and documentation for preparing, testing, and standardizing laboratory reagents and reference standards.

Production and process controls. FDA will verify that each facility has appropriate systems in place to ensure that production and process controls are followed and documented at the time of performance. Appropriate SOPs and specifications should have been established to monitor the performance of processes that can affect variability in the characteristics of a drug or biologic product. Inspectors will review process validation protocols, testing data and documentation, and final reports to determine if there is documented evidence that processes can consistently produce a product that meets predetermined specifications and quality attributes. They will likely review the adequacy of procedures in place for documenting any deviations and will determine whether adequate documentation exists to justify decisions. Team Biologics will give priority attention to evidence of deviations or discrepancies not adequately investigated by a company (or incomplete documentation). If the agency finds repeated documentation discrepancies or egregious instances of improper actions, Team Biologics members are likely to recommend regulatory sanctions as described in the Team Biologics program (1).

Reprocessing, reworks, returned goods, and rejected materials. Team Biologics will give considerable attention to situations in which companies are reprocessing or reworking in-process batches or finished products that do not meet specifications. Of particular concern to FDA will be whether the reprocessing or reworking process is defined in an application that has been approved by FDA. If Team Biologics finds that batches failing specifications have been reprocessed or reworked by an unapproved process (that is, if the methods, controls, or parameters differ from the approved process) or by processes that have not been validated, FDA will consider that to be a serious regulatory issue and will likely collect evidence to support potential regulatory sanctions.

Prudent companies will review existing procedures and completed batch records to verify conformance with regulatory commitments and to verify that reprocessing or reworking processes are supported with documented evidence of validation. If reprocessed or reworked batches are detected that do not meet regulatory commitments (or processes were not validated), companies should seek legal counsel and determine the appropriate actions (recall affected products, validate the process, update applications, or take other actions as appropriate). FDA may review SOPs that relate to processing materials that have been returned or that do not meet specifications. Inspectors will be especially alert for evidence of reprocessing or reworking batches that do not meet specifications where there may not be an adequate documented investigation or where unvalidated processes were used to rework or reprocess nonconforming products.

Record-keeping practices. Team Biologics will focus on documentation and SOPs with the approaches that have been used by ORA field investigators for many years. Some biologics companies may find that priorities differ from their previous experiences with CBER personnel. Team Biologics will determine whether there are effective policies and procedures for maintaining records covering the production and control of drug or biologic products and ensure that such records are readily available for inspection. Special attention will be given to reviewing original records for analytical testing, in-process batch production and control records, validation documentation, and others. For example, FDA will evaluate record-keeping systems covering OOS and failure investigations and the steps taken to correct failures of drug or biologic products to meet specifications. FDA will be especially alert to determine whether the investigations have extended to other batches or similar products that may be affected by the nonconforming results. Also, FDA may perform data audits to verify the adequacy of techniques used to enter, store, and retrieve raw data and original information during production and control activities.

Buildings, facilities, and equipment. Team Biologics members will examine each building used in the production and control of drug or biologic products to determine whether it is of suitable design, size, construction, and location to ensure effective maintenance and cleaning and proper operation for its intended use. Included in this review will be a systematic evaluation of the design and maintenance of utility systems such as purified water, water-forinjection, compressed gasses, and HVAC and HEPA systems to ensure that aseptic processes are carried out under suitable environmental conditions. For biologic products, special attention will be given to aseptic process validation and the controls used to ensure effectiveness of viral inactivation. For example, FDA will be alert to employee practices and construction defects that may allow the potential for viral contamination (such as exposure to environment after viral inactivation, ineffective or nonvalidated processes for inactivation, or inappropriate employee practices).

FDA will look for any equipment that is not suitable for its intended purpose or is not of suitable design, size, and construction to allow proper maintenance, cleaning, and performance, especially in older facilities where equipment may not have been upgraded to current industry standards. Inspectors may identify the computer systems that are used in production and control and verify that validation and qualification data are sufficient to demonstrate that the systems operate reliably. Depending on the focus of the inspection, Team Biologics members may review qualification (installation, operation, and performance qualification protocols and the corresponding testing data and final reports) of key equipment. Biologics companies that installed equipment many years ago may find they do not have IQ, OQ, and PQ data or reports or that they have made changes to the equipment. Such companies should be prepared to demonstrate that equipment can perform its intended functions uniformly and reliably. Retrospective qualification and validation is theoretically possible but will be of questionable validity if FDA detects changes to the equipment or processes.

Employee training. Team Biologics members are always alert for evidence that employees may not have the education, training, and experience to carry out their duties and responsibilities. FDA will observe employee behavior and actions to verify that personnel are familiar with and follow SOPs within their areas of responsibilities. FDA expects that each employee will have documented evidence of GMP training, that such training is described in procedures, and that personnel are supported with continuing education and training to keep their skills in line with advances in quality practices and CGMPs. FDA may give special attention to new employees, temporary staff, and contractors to verify that they have documented evidence of training before assuming functions involved with production and control of biologics.

Roles amd responsibilities of QA and QC. Inspectors may review company policies and procedures to determine that they establish uniform, mandatory standards for GMP compliance. They will be alert to evidence of areas where certain GMP responsibilities may not have been adequately defined (such as all facets of compliance monitoring; procedures used to monitor complaints; reports of adverse experiences; and investigations of product or process failures and other quality-related issues that affect the safety, identity, strength, and purity of drug and biologic products). FDA will review SOPs and specifications to ensure that they are up-todate and that they accurately reflect requirements. FDA will determine whether there are written SOPs that require filing reports under 21 CFR Parts 600.80, 314.70, and others (as appropriate) to ensure compliance with regulatory requirements.

Team Biologics will look for documented evidence that the Quality Control Unit is empowered to fully and effectively carry out their responsibilities as set forth in 21 CFR 211.22. Some teams may audit the overall organizational structure and evaluate the specific responsibilities of each work unit involved in the production of biologicals. FDA expects biologics manufacturers to have procedures in place for detecting and correcting any deficiencies that are noted on FDA 483s and internal audits.

Preparing for Success

This article began with a brief review of the parallels between what is currently happening in the biologics industry and what happened to other segments of the pharmaceutical industry when FDA initiated directed inspections by teams made up of specialists. I believe that history is repeating itself with Team Biologics.

Under Team Biologics, a number of companies are sure to experience serious regulatory challenges and/or legal sanctions. But proactive steps can be taken to reduce or eliminate the risk of an unsuccessful inspection. By publishing the Team Biologics initiative and its schedule for implementation (see the "Team Biologics Inspection Schedules" box), FDA has served its notice, and prudent companies will heed the warning and act accordingly.

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References

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(1) FDA, "A Plan for Reinventing FDA's Ability to Optimize Compliance of Regulated Biologics Industries," Updated 10 November 1997. Available on internet at www.fda.gov/cber/genadmin/teambio.htm.

(2) R.F. Tetzlaff, R.E. Shepherd, and A.J. LeBlanc, "The Validation Story: Perspectives on Systematic GMP Inspection Approach and Validation Development," Pharm. Technol. 100116 (1993).

(3) "Human and Veterinary Drugs, Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding," Federal Register 43, 190 (29 September 1978), pp. 45014-45089.

(4) FDA, "Pre-approval Inspections/ Investigations," Compliance Program, CP 7346.832, Chapter 46, New Drug Evaluation (August 1994).

(5) S. Gray, "FDA's International GMP Inspections," paper presented at International GMP Conference, Athens, GA, 4-7 March 1996.

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(6) Office of Inspector General, "Review of the Food and Drug Administration's Inspection Process of Plasma Fractionators," Gibbs Brown, Inspector General, Report A-03-9700350 (June 1997).

(7) T. Roslewicz, "Testimony before the Committee on Government Reform and Oversight, Subcommittee on Human Resources, FDA Regulation of Blood Safety, Statement of Thomas D. Roslewicz," Office of the Inspector General (5 June 1997).

(8) P.A. Peterson, "BioPharm Conference '98: PC3," presentation at BioPharm Conference, San Francisco, CA, 4-6 May1998.

(9) FDA, "Adulteration of Drugs Under Section 501(b) and 501(c) of the Act. Direct Reference Seizure Authority for Adulterated Drugs Under Section 501(b)," Compliance Policy Guide 7132a.03 (1 May 1992).

(10) "Fraud, Untrue Statements of Material Facts, Bribery and Illegal Gratuities; Final Policy,"

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Federal Register 56, 175 (10 September 1991) Docket 90N-0332.

(11) FDA, "Fraud, Untrue Statements of Material Facts, Bribery and Illegal Gratuities," Compliance Policy Guide, 7150.09 (July 1991).

(12) FDA, "Points to Consider for Internal Reviews and Corrective Action Plans" (Bethesda, MD, June 1991).

(13) FDA, "DEBARMENT LIST' (updated 16 June 1998). Public listing of companies or persons debarred pursuant to sections 306(a) and (b) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 335(a) and (b)], www.fda.gov/ora/compliance_ref/debar/debar. txt.

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(14) FDA, Internet site listing drug and medical device companies currently under Application Integrity Policy www.fda.gov/ora/ compliance_ref/aiplist05l9.html. (15) FDA, Internet site, FDA Enforcement Reports,

www.fda.gov/opacomlEnforce.html. (16) The Gold Sheet, "Recall Trend Continues Downward in 1995," 30 (1), January 1996. (17) The Gold Sheet, "Change Controls Draw FDA

Enforcement Action," 29 (9), September 1995. (18) The Gold Sheet, "AADA Deviations Spur Drug Product Recalls," 32 (1), January 1998. (19) J.G. Dickinson, "38 Device Frauds Probed by

FDA," MD&DI 34-35 (June 1996). (20) D. Michels, "FDA's Enforcement Program," RA Focus 2 (7) (July 1997).

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[Author Affiliation]

eoN id F. Tittlo is vice president of compliance services at KMI/Parexel, Inc., 1303 Hightower Trail, Suite 330, Atlanta, GA 30350, (770) 641-9100, fax (770) 992-4002, rtetzlaff@belmont.kminc.com.