7345.848 - Inspection of Biological Drug Products

7345.848 -  Inspection of Biological Drug Products
From FDA - May 23, 2017

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Compliance Program Guidance Manual
Chapter45 Biological Drug Products

Implementation Date: October 1, 2010

Completion Date: Ongoing

FIELD REPORTING REQUIREMENTS

Send Establishment Inspection Reports (EIRs) that contain issues requiring policy development or clarification to the Center for Biologics Evaluation and Research (CBER) for review. Send the EIR and relevant exhibits (electronically, if possible), to CBERInspections@fda.hhs.gov, or by mail to:

Division of Inspections & Surveillance, HFM-650
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448

Domestic Post-Market Inspections:

Inspections classified NAI and VAI: Notify CBER, Office of Compliance and Biologics Quality (OCBQ), Division of Inspections and Surveillance (DIS) HFM-650 at CBERInspections@fda.hhs.gov, when EIRs are available in Turbo EIR.* Do not submit exhibits unless specifically requested.

Inspections classified OAI: Send a complete copy of the EIR, including exhibits, and the FACTS coversheet with endorsement and classification to OCBQ/DIS/HFM-650.

Regardless of classification, send the complete original report, with exhibits, to the home district.

Foreign Post-Market Inspections:

CBER acts as the home district for foreign inspections of CBER-regulated products. Send the complete original EIR, with exhibits, to OCBQ/DIS/HFM-650, regardless of recommended classification.

Pre-license and Pre-approval Inspections

CBER acts as the "home district" for all pre-license and pre-approval inspections of CBER-regulated products, whether foreign or domestic. Send a copy of the signed original EIR and Form FDA 483 to OCBQ/DIS/HFM-650 and include the complete original EIR, with exhibits, in the license application file documents as per current CBER standard operating procedures.

Inspection ReportingEndorsement Section of EIR

The FACTS endorsement (Inspection Summary field) shall include the inspection level and the systems inspected for a level II inspection in addition to the information specified in the Investigations Operations Manual (IOM).

TABLE OF CONTENTS

PART I - BACKGROUND

PART II- IMPLEMENTATION

A. OBJECTIVE
B. STRATEGY
C. PROGRAM MANAGEMENT INSTRUCTIONS

1. Precautionary Measures

2. Frequency of CGMP Inspections

3. Scheduling of Inspections and Assignment of Investigators

PART III - INSPECTIONAL

A. INSPECTIONAL PROCEDURES
B. SYSTEMS DEFINITION
C. INSPECTION COVERAGE

D. INSPECTION APPROACHES

E. INSPECTIONAL GUIDANCE

F. REPORTING

Part IVANALYTICAL

PART V - REGULATORY/ADMINISTRATIVE STRATEGY

PART VI - REFERENCES AND PROGRAM CONTACTS

A. REFERENCES:
B. PROGRAM CONTACTS:

PART VIICOORDINATION AND PROGRAM MONITORING

ATTACHMENTS - Product Guidance

ATTACHMENT 1: FRACTIONATORS
ATTACHMENT 2: VACCINES
ATTACHMENT 3: RECOMBINANT PRODUCTS
ATTACHMENT 4: ALLERGENICS
FLOW DIAGRAM
APPENDICES TO FLOW DIAGRAM
ATTACHMENT 5: MINIMALLY MANIPULATED, UNREALTED ALLOGENEIC UNBILICAL CORD BLOOD (HEMATOPOIETIC PROGENITOR CELLS, CORD [HPC-C])
ATTACHMENT 6: PRE-LICENSE AND PRE-APPROVAL INSPECTIONS

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PART I - BACKGROUND

CBER-regulated biological drug products include fractionated blood and their recombinant analogues; antitoxins; allergenic products; vaccines; products of CBER-regulated biological drug products include fractionated blood and their recombinant analogues; antitoxins; allergenic products; vaccines; products of manipulated, cultured or expanded human cells, and gene therapy products that introduce genetic material into the body to replace faulty or missing genetic material.

CBER is responsible for ensuring biological drug products are safe and effective, and are in compliance with FDA and other applicable laws and regulations. Biological drug products are licensed under Section 351 of the Public Health Service (PHS) Act (42 U.S.C), and fall within the definition of a drug, found in Section 201(g)(1) of the Food, Drug, and Cosmetic Act (FD&C Act), and are inspected under the provisions of both the PHS Act and the FD&C Act.

Biological drug products are subject to the applicable regulations promulgated under both Acts, including the Current Good Manufacturing Practice regulations (CGMPs), which are found in Title 21 Code of Federal Regulations (CFR), Parts 210 and 211, and the Biologics regulations, 21 CFR Parts 600-680. In addition to the above, human cells, tissues, and cellular and tissue-based products regulated as biological drug products are also subject to the Registration and Listing, Donor Eligibility, and Current Good Tissue Practice (CGTP) regulations in 21 CFR Part 1271. Section 501(a)(2)(B) of the FD&C Act requires that biological drug products be manufactured in compliance with CGMPs. CGMP regulations apply to the manufacture of biological drug products and CGMP principles apply for the manufacture of biological intermediates and drug substances under Section 501(a)(2)(b) of the FD&C Act, and the Biologics regulations under 21 CFR Part 600.

Establishments must also comply with their FDA-approved biologics license application (BLA) commitments, and applicable standards. Biological drug products include a wide variety of indications, dosage forms and manufacturing processes, all of critical importance to promoting and protecting the public health. To help ensure the industry produces these important biological drugs to be consistently safe, pure, potent, and effective, FDA conducts CGMP inspections of each establishment at least biennially. Pre-license inspections (PLI) for new biological products and pre-approval inspections (PAI) for significant changes to a biologics license application are performed to ensure compliance with the regulations prior to approval of a new license or significant change to the license.

To provide more effective and efficient regulation of biological drug products, the Office of Regulatory Affairs (ORA) and CBER established Team Biologics in 1997 to conduct routine and compliance follow up CGMP inspections of biological drug product manufacturers, including blood establishments. Team Biologics uses the investigative skills of ORA and the medical/scientific and product expertise of CBER, to promote and protect the public health through coordinated, integrated assessments of the compliance status of biological drug manufacturers. CBER conducts the PLIs and PAIs utilizing the CGMP requirements and the scientific expertise of CBER reviewers.

This compliance program builds upon the knowledge gained during previous FDA inspections of the biological drug and tissue industries. It reflects the objectives identified in FDAs Strategic Action Plan for developing and implementing new inspection approaches using a resource efficient, risk-based approach to provide high quality, cost-effective oversight of industry manufacturing, processing, and distribution of biological drug products to reduce risk.

This systems-based risk-management approach identifies key systems and three critical elements within each system that are common to establishments making biological drug products. Most biological drug products covered under this compliance program were identified as critical to public health (e.g., sole source, important medical need; childhood vaccines, etc.), and most biological drug products are aseptically processed. These factors help form the basis for establishing appropriate levels of inspection coverage under this risk-based program.

This program also establishes two levels of inspectional coverage to evaluate an establishments compliance with applicable CGMP regulations; Level I (Full)a comprehensive evaluation of at least four systems, and Level II (Abbreviated)an evaluation of one mandatory system, plus one additional system on a rotating basis. This approach is similar in concept to that set forth in CBERs CPG 7342.001- Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors, that incorporates a systems-based approach with critical elements to be covered within each system, and a Level I/II inspection option.

This risk-based quality management approach focuses on the key operating systems within the facilities and the two-tiered inspection option provides a method to focus the inspectional coverage and resources appropriate for each inspection, and to implement the appropriate advisory, administrative, or regulatory action, when necessary.

Continued biennial inspections under this compliance program will:

Subsequent to implementation, CBER will annually evaluate its experience with this systems-based program to determine its effectiveness, and to assess and improve the quality of the CBER products inspections program.

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PART II- IMPLEMENTATION

A. OBJECTIVE

Beginning in December 2004 this compliance program originally combined and replaced the compliance programs for licensed allergenics (7345.001), licensed vaccines (7345.002), plasma derivatives (7342.006) and therapeutic drugs (7341.001). This current version adds, for the first time, minimally manipulated, unrelated allogeneic placental/umbilical cord blood (Hematopoietic Progenitor Cells, Cord [HPC-C]). This program represents a continuing compliance and surveillance activity conducted to ensure that CBER-regulated biological drug products for human use are safe, pure, potent, effective, and appropriately labeled. The inspection of a facility is performed to ensure that manufacturers are making biological drug products that:

This compliance program provides inspectional guidance to investigators, inspectors, and product specialists assigned to perform biennial, for cause, PLI, and PAI inspections of manufacturers of CBER-regulated biological drug products, and provides administrative/regulatory guidance for the compliance officer (CO) or investigator (hereinafter referred to as investigators). It includes information regarding noncompliance with applicable regulations, provides information necessary to evaluate overall operations, including quality assurance and quality control programs of the inspected facilities, and ensures that appropriate enforcement actions are initiated against those manufacturers found to be in significant noncompliance with applicable laws and regulations.

Firms covered under this compliance program include the following: all licensed manufacturers of vaccines and related biological drug products, including source material manufacturers and licensed bulk manufacturers; all licensed manufacturers of allergenic products (allergenic patch test manufacturers are not included); unlicensed source material suppliers; all licensed manufacturers of fractionated products, certain recombinant products, and certain human cell, tissue, and cellular and tissue-based products (HCT/Ps) regulated as drugs, and/or biological products.

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B. STRATEGY

This compliance program incorporates a systems-based, risk management approach to conducting inspections, and identifies key systems and three critical elements within each system for inspection.

The key systems are:

The three critical elements are:

The inspection of biological drug manufacturers is conducted under either a Level I (Full) or Level II (Abbreviated) inspection option. This compliance program directs an in-depth audit of the critical elements in each key system, which may affect the safety, purity, potency, identity, and effectiveness of the biological drug, if procedures are not performed properly or the system controls are either inadequate or not functioning correctly.

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C. PROGRAM MANAGEMENT INSTRUCTIONS

1. Precautionary Measures/Personal Safety Issues

Due to the nature of the materials used to manufacture certain biological drug products, investigators may be required to provide proof of inoculation against a particular disease agent or undergo certain medical evaluations prior to beginning an inspection. Investigators should be aware of any such requirements and ensure they are met in sufficient time prior to the start of the inspection, so as to make certain the inspection schedule will not be disrupted.

Additionally, in many cases, the active materials used to manufacture biological drug products are potentially hazardous to the health in their initial form. For this reason, investigators must exercise extreme care when performing inspections of manufacturing areas to ensure they do not come into direct contact with these materials and maintaining universal precautions.

2. Frequency of CGMP Inspections

CGMP inspections are statutory obligations that are routinely conducted on a biennial schedule; however, inspections may be conducted more often if circumstances, such as the firms compliance history, so warrant.

Exceptions:

This inspectional frequency does not apply to firms that meet the following conditions; additionally, these firms must be inspected using the Level I Inspection Option.

3. Scheduling of Inspections and Assignment of Investigators

Under Team Biologics, the Team Biologics (TB) Supervisor (or designee) works with CBER/OCBQ/DIS to develop the workplan schedule of inspections, and to ensure CBER product specialist participation, either on-site or by consult, in CGMP inspections. All parties attempt to minimize rescheduling of inspections, but changes are at times necessary. The TB Supervisor promptly notifies and consults with CBER regarding schedule changes.

After reviewing the establishments inspectional history and other relevant information, biological drug product manufacturers will be scheduled for either a Level I or Level II inspection.

The inspections will be conducted using a team approach with a Team Biologics investigator leading, and a CBER product specialist participating. The inspection team may include other ORA or CBER members, as necessary, to ensure appropriate coverage of the facility being inspected. If CBER on-site participation is not possible, the Team member(s) alone will conduct the inspection with participation of product specialist off-site (e.g., telephone).

Other inspections:

CBER is responsible for the conduct of all PLI and PAI inspections of CBER-regulated biological drug products. These inspections are part of the review of a BLA or supplement. CBER identifies the scope and content of the inspection and invites ORA to participate in the inspections. CBER/OCBQ, Division of Manufacturing and Product Quality (DMPQ) will notify the district office and the TB Supervisor of all pending pre-license or pre-approval inspections.

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PART III - INSPECTIONAL

A. INSPECTIONAL PROCEDURES

Review and use the applicable sections of Chapter 5 of the Investigations Operations Manual (IOM); Compliance Program 7356.002, Drug Manufacturing Inspections; 7356.002A, Sterile Drug Process Inspections; guidance applicable to the manufacture of CBER regulated biological drug products, and other pertinent documents provided by CBER. If there are differences between the above referenced documents and the instructions in this program, investigators should follow the instructions in this program when conducting inspections.

Source material suppliers for vaccine, allergenic, and fractionated products are subject to the requirements in 21 CFR Parts 600-680. Source material suppliers for HPC-C products are subject to 21 CFR Part 1271. Because they are not finished product manufacturers, the drug CGMP regulations in Parts 210 and 211 may not be directly applicable. However, they are required to comply with CGMPs in the context of section 501(a)(2)(B) of the Act, to ensure the products have the quality, purity, and identity they purport. If there are questions regarding the appropriateness of one or more particular inspectional observations relating to a source material supplier, such as suppliers of animal source materials for animal derived products, e.g., antitoxin and porcine Factor VIII, the Team Biologics CO should review the observation(s) before inclusion on the Form FDA 483, Inspectional Observations.

If it is necessary to verify the content of a license application or supplement or if there is an apparent conflict between the approved license and any FDA guidance documents or regulations, contact CBER/OCBQ/DIS, and the relevant product office for assistance.

The Team Biologics lead investigator with the inspection team members, product specialist(s), CBER/OCBQ/DIS and the home district, if applicable, will develop the overall inspectional approach for individual CGMP inspections. Products needing special coverage will be addressed as part of the specific inspectional approach. A similar approach is applied to CBER PLIs and PAIs with CBER/OCBQ/DMPQ and the product specialist reviewer for the submission.

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B. SYSTEMS DEFINITION

Inspections of biological drug product manufacturers are to be conducted and reported using the systems and organization defined in this compliance program. In addition to the areas of inspectional focus described below for each system, system assessment should include a walk- through of the facilities whenever possible.

1. Quality System

This system assures overall compliance with CGMPs, internal procedures, and adherence to specifications. It includes, but is not limited to the following: the quality control unit (QC) and all of its review and approval duties; such as release of components and in-process materials, change control, reprocessing, batch release, annual record review, validation protocols and reports; all BPD evaluations; complaint handling, and evaluation of returned and salvaged products, including evidence of counterfeit products.

Assessment of the Quality System is two-phased. The first phase is to evaluate whether the QC unit has fulfilled its responsibility to review and approve all procedures related to production, quality control and quality assurance, and to ensure the procedures are adequate for their intended use. This also includes the associated record keeping systems.

Review records related to product recall, product deviations, complaints, out of specification results, rejects, and failure investigations. Verify the firm routinely reviews its records pertinent to the manufacture of lots or units prior to their release or distribution. Examine, report, and track counterfeit imported products, returned and rejected imported products, and complaint files concerning imported products. The second phase is to assess the data collected in order to identify quality problems that may be linked to other systems.

2. Facilities and Equipment System

This system includes the measures and activities that provide an appropriate physical environment, along with the equipment and resources that are used in the production of the biological drug product.

Coverage of this system should include verifying the appropriateness of buildings and facilities, including maintenance; equipment qualifications (installation and operation); equipment calibration and preventative maintenance; cleaning and validation of cleaning processes as appropriate; prevention of contamination and cross contamination; extractable and leachable or other contaminants on product contact equipment causing deterioration or rendering product less suitable for intended use; and utilities that are not intended to be incorporated into the product; such as HVAC, compressed gases, and steam and water systems. Process performance should be evaluated as part of the inspection of the overall process, which is done within the system where the process is employed.

3. Materials System

This system includes the measures and activities to control finished products, such as components, source materials, water or gases that are incorporated into the product, and containers and closures. The audit of this system should include examining the validation of computerized inventory control processes, product storage, distribution controls, records, and detection and prevention of counterfeiting, including counterfeit imported materials. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturer's recommendations and/or user manuals. In addition, the audit should verify whether equipment has been adequately qualified for its intended use, if necessary, and if any new equipment was added or any modifications to existing equipment were made since the last inspection.

4. Production System

This system includes the measures and activities to control the manufacture of biological drug products, including following and documenting performance of approved manufacturing procedures. Inspection of this system should include, among other things, batch formulation; dosage form production; sterile filtration; aseptic filling; in-process testing; lot release, and process validation.

Review a sampling of records for operations performed. Verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries; show test results as well as the interpretation of results; show the expiration date assigned to specific products; and be as detailed as necessary to provide a complete history of the work performed.

Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturer's recommendations and/or user manuals. In addition, the audit should verify whether equipment has been adequately qualified for its intended use, if necessary, and if any new equipment was added or any modifications to existing equipment were made since the last inspection.

5. Packaging and Labeling System

This system encompasses the measures and activities that control packaging and labeling of biological drug products. Inspectional coverage should include review of the firm's written procedures regarding packaging and labeling controls, for example, procedures that are in place to prevent label mix-ups, document appropriate label storage, and issuance and destruction of labels after use as well as removal of labels from a manufacturing area. The firm's examination of labels and usage, and label storage and issuance should also be observed during the inspection. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical and/or manufacturing changes. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturer's recommendations and/or user manuals. In addition, the audit should verify whether equipment has been adequately qualified for its intended use, if necessary, and if any new equipment was added or any modifications to existing equipment were made since the last inspection.

6. Laboratory Control System

This system includes all the various measures and activities that are related to laboratory procedures; analytical methods development; validation or verification; and the stability program. An in-depth audit of this system should include review of the firm's SOPs for control of microbiological contamination and environmental monitoring; review of records for source materials, in-process and finished product testing; evaluation of the firm's methods for sampling and testing products for identity, potency, safety, sterility and conformance with final specifications; and review of the firm's test methods to ensure that they have been appropriately validated.

Review a sampling of records for operations performed; verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries.

Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the anufacturer's recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection.

7. Donor Eligibility System

This system includes the measures and controls that are related to determining the eligibility of a donor of allogeneic and family-related allogeneic HCT/P products, including donor screening and testing. Inspectional coverage should include review of the firm's written procedures for all steps performed in screening, testing, and determining donor eligibility. Inspections should include a review of a sampling of records related to the donor eligibility determination, including the name of the responsible person that made the determination, and the results and interpretation of all donor screening and testing for relevant communicable disease agents. Inspectional coverage should include verification that records are complete and maintained as required, and are related to the history and disposition of all biological drug products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries; and be as detailed as necessary to provide a complete history of the work performed.

The audit of this system should also assess the firm's procedures for quarantine of biological drug products pending completion of the donor eligibility determination, the identification and storage of products from donors determined to be ineligible, and the labeling and limited use of such products under the provisions of urgent medical need.

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C. INSPECTION COVERAGE

1. Precautionary Measures

Due to the nature of the materials used to manufacture certain biological drug products, investigators may be required to provide proof of inoculation against a particular disease agent or undergo certain medical evaluations prior to beginning an inspection. Investigators should be aware of any such requirements and en sure they are met in sufficient time prior to the start of the inspection, so as to make certain the inspection schedule will not be disrupted.

Additionally, in many cases, the active materials used to manufacture biological drug products are hazardous to the health in their initial form. For this reason, investigators must exercise extreme care when performing inspections of manufacturing areas, to ensure they do not come into direct contact with these materials.

2. Frequency of CGMP Inspections

CGMP inspections are statutory obligations that are routinely conducted on a biennial schedule; however, inspections may be conducted more often if circumstances, such as the firms compliance history, so warrant.

Exceptions:

This inspectional frequency does not apply to firms that meet the following conditions; additionally, these firms must be inspected using the Level I Inspection Option.

3. Scheduling of Inspections and Assignment of Investigators

Under Team Biologics, the Team Biologics (TB) Supervisory (or designee) works with CBER/OCBQ/DIS to develop the workplan schedule of inspections, and to ensure CBER product specialist participation, either on-site or by consult, in CGMP inspections. All parties attempt to minimize rescheduling of inspections, but changes are at times necessary. The TB Supervisory promptly notifies and consults with CBER regarding schedule changes.

After reviewing the establishments inspectional history and other relevant information, biological drug product manufacturers will be scheduled for either a Level I or Level II inspection.

The inspections will be conducted using a team approach with a Team Biologics Core Team investigator leading, and a CBER product specialist participating. The inspection team may include other ORA or CBER members, as necessary, to ensure appropriate coverage of the facility being inspected. If CBER on-site participation is not possible, the Core Team member(s) alone will conduct the inspection, with participation of product specialist off-site (e.g., telephone).

Other inspections:

CBER is responsible for the conduct of all pre-license (PLI) and pre-approval (PAI) inspections of CBER-regulated products. These inspections are part of the review of a BLA or supplement. CBER identifies the scope and content of the inspection and invites ORA to participate in the inspections. CBER/OCBQ, Division of Manufacturing and Product Quality (DMPQ) will notify the district office and the TB Supervisory Investigator of all pending pre-license or pre-approval inspections.

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PART III - INSPECTIONAL

A. INSPECTIONAL PROCEDURES

Review and use the applicable sections of Chapter 5 of the Investigations Operations Manual (IOM); Compliance Program 7356.002, Drug Manufacturing Inspections; 7356.002A, Sterile Drug Process Inspections; guidance applicable to the manufacture of CBER regulated drug products, and other pertinent documents provided by CBER. If there are differences between the above referenced documents and the instructions in this program, investigators should follow the instructions in this program when conducting inspections.

Source material suppliers are subject to the requirements in 21 CFR Parts 600-680. Because they are not finished product manufacturers, the drug CGMP regulations in Parts 210 and 211 may not be directly applicable. However, they are required to comply with CGMPs in the context of section 501(a)(2)(B) of the Act, to en sure the products have the quality, purity, and identity they purport. If there are questions regarding the appropriateness of one or more particular inspectional observations; relating to a source material supplier, such as suppliers of animal source materials for animal derived products, e.g., antitoxin and porcine Factor VIII; the Team Biologics CO should review the observation(s) before inclusion on the Form FDA 483, Inspectional Observations.

If it is necessary to verify the content of a license application or supplement or if there is an apparent conflict between the approved license and any FDA guidance documents or regulations, contact CBER/OCBQ/DIS, and the relevant product office for assistance.

The Team Biologics Core Team, including the appropriate product specialist, in conjunction with CBER/OCBQ/DIS and the home district, will develop the overall inspectional approach for individual CGMP inspections. Products needing special coverage will be addressed as part of the specific inspectional approach.

Back to the Top

B. SYSTEMS DEFINITION

Inspections of biological drug product manufacturers are to be conducted and reported using the systems and organization defined in this compliance program. In addition to the areas of inspectional focus described below for each system, system assessment should include a walk-through of the facilities whenever possible.

1. Quality System

This system assures overall compliance with CGMPs, internal procedures, and adherence to specifications. It includes, but is not limited to the following: the quality control unit (QC) and all of its review and approval duties; such as release of components and in-process materials, change control, reprocessing, batch release, annual record review, validation protocols and reports; all BPD evaluations; complaint handling, and evaluation of returned and salvaged products, including evidence of counterfeit products.

Assessment of the Quality System is two-phased. The first phase is to evaluate whether the QC unit has fulfilled its responsibility to review and approve all procedures related to production, quality control and quality assurance, and to ens ure the procedures are adequate for their intended use. This also includes the associated record keeping systems.

Review records related to product recall, product deviations, complaints, out of specification results, rejects, and failure investigations. Verify the firm routinely reviews its records pertinent to the manufacture of lots or units prior to their release or distribution. Examine, report, and track counterfeit imported products, returned and rejected imported products, and complaint files concerning imported products. The second phase is to assess the data collected in order to identify quality problems that may be linked to other systems.

2. Facilities and Equipment System

This system includes the measures and activities that provide an appropriate physical environment, along with the equipment and resources that are used in the production of the biological drug product.

Coverage of this system should include verifying the appropriateness of buildings and facilities, including maintenance; equipment qualifications (installation and operation); equipment calibration and preventative maintenance; cleaning and validation of cleaning processes as appropriate, and utilities that are not intended to be incorporated into the product; such as HVAC, compressed gases, and steam and water systems. Process performance should be evaluated as part of the inspection of the overall process, which is done within the system where the process is employed.

3. Materials System

This system includes the measures and activities to control finished products, such as components, source materials, water or gases that are incorporated into the product, and containers and closures. The audit of this system should include examining the validation of computerized inventory control processes, product storage, distribution controls, records, and detection and prevention of counterfeiting, including counterfeit imported materials. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection.

4. Production System

This system includes the measures and activities to control the manufacture of biological drug products, including following and documenting performance of approved manufacturing procedures. Inspection of this system should include, among other things, covering batch formulation; dosage form production; sterile filtration; aseptic filling; in-process testing; lot release, and process validation.

Review a sampling of records for operations performed. Verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries; show test results as well as the interpretation of results; show the expiration date assigned to specific products; and be as detailed as necessary to provide a complete history of the work performed.

Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection.

5. Packaging and Labeling System

This system encompasses the measures and activities that control packaging and labeling of biological drug products. Inspectional coverage should include review of the firms written procedures regarding packaging and labeling controls. The firms examination of labels and usage, and label storage and issuance should also be observed during the inspection. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection.

6. Laboratory Control System

This system includes all the various measures and activities that are related to laboratory procedures; analytical methods development; validation or verification; and the stability program. An in-depth audit of this system should include review of the firms SOPs for control of microbiological contamination and environmental monitoring; review of records for source materials, in-process and finished product testing; evaluation of the firms methods for sampling and testing products for identity, potency, safety, sterility and conformance with final specifications; and review of the firms test methods to ensure that they have been appropriately validated.

Review a sampling of records for operations performed verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries.

Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment used in support of this system must be maintained in a clean and orderly manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection.

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C. INSPECTION COVERAGE

For each of the systems defined above, the inspection must include, coverage of the following three critical elements: (1) procedures, (2) training/personnel, and (3) records. Actual observations of the processes applicable to each system should be performed whenever possible. Because most biological drug products covered by this program are aseptically processed, inspectional guidance for coverage of facilities, equipment calibration, and equipment
maintenance has been incorporated into the systems, as appropriate.

1. Standard Operating Procedures (SOPs)

For each of the systems the firm should have approved written procedures and associated records, e.g., testing, maintenance, cleaning, etc., that document adherence to the procedures. Investigators should verify through actual observation, whenever possible, whether or not the firm adheres to the approved written procedures.

2. Training/Personnel

The organization and personnel, including appropriate qualifications and training employed in any given system, should be evaluated as part of that system's operation.

3. Records

Records must be maintained concurrently with the performance of each significant step in the processing, testing, and distribution of biological drug products so all steps can be clearly traced and documented. If any records, which are required by regulation, are maintained in an electronic format in place of paper format, the record keeping system should comply with 21 CFR Part 11 (see Guidance for Industry, Part 11, Electronic Records; Electronic Signatures -
Scope and Application, August 2003).

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D. INSPECTION APPROACHES

This compliance program provides two surveillance inspection options, Level I, and Level II; both the Level I and Level II option satisfy the biennial inspection requirement.

Level I (Full) Inspection Option

The Level I (Full) option is a surveillance or compliance inspection that is meant to provide a comprehensive evaluation of the establishment's overall compliance with applicable CGMP requirements.

Level I inspections apply to one or more of the following conditions:

The Level I option includes an in-depth audit of the three critical elements in at least four of the systems, one of which must be the Quality System. In addition to the audit of the Quality System, Level I inspections of biological drug product manufacturers should also include an audit of the Production System, except for manufacturers of HPC-C, where Level I inspections should also include an audit of the Production System and Donor Eligibility System.

If investigators observe serious deficiencies in one or more systems during the course of a Level I inspection, they may, after consult with an ORA/OE Compliance Officer, revert to the Level II inspection option, provided a minimum of two systems are completed. The consultation should also include discussion of the necessary documentation to support a possible enforcement action.

Level II (Abbreviated) Inspection Option

The Level II (Abbreviated) option is a focused surveillance CGMP inspection that covers two of the key systems, and provides verification of an establishment's continued compliance with CGMP. This option also includes inspectional coverage of any significant changes to the facilities, manufacturing process, equipment, or other license supplements since the preceding inspection.

The Level II option includes an in-depth audit of the three critical elements of the Quality System, and one additional system must be selected for coverage during the inspection, which will be determined during work planning. Coverage of additional systems should be rotated in successive Level II inspections, unless otherwise indicated by issues identified during the current or previous inspection. In addition, during the course of a Level II inspection, verification of QA activities may require limited coverage of other systems.

Select a Level II Option for any one of the following situations*:

* Until further notice the Level II inspection option should not be utilized for HPC-C establishments.

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E. INSPECTIONAL GUIDANCE

1. Cooperative Manufacturing Arrangements: For further guidance, see: Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics

i. SHARED MANUFACTURING

In a shared manufacturing arrangement, each manufacturer is licensed to perform part of the manufacturing of a product, but no one manufacturer is licensed for the entire process. Each manufacturer in a shared arrangement submits a separate license application, and the approval of the product is based on information from each application.

The manufacturer who prepares the product in its final form will be held responsible for any post-approval obligations, such as reporting biological product deviations and adverse events, unless the manufacturers agree and the approved application says otherwise. Investigators should determine if the agreements in the applications are being met, particularly as they pertain to the integrity of the product.

ii. DIVIDED MANUFACTURING

In a divided manufacturing arrangement, each manufacturer is licensed to manufacture a product in its entirety, but each performs only part of the process. This arrangement is described in supplements submitted to each manufacturer's license. The record requirements for divided manufacturing arrangements are described in 21 CFR 600.12(e). Each manufacturer must have documentation of its responsibility for manufacturing the product.

The manufacturer who makes the product in final form must retain a complete set of manufacturing records for all operations relating to the product, including those operations performed at another facility. Investigators should thoroughly review the divided manufacturing arrangement and determine if the process; as described in the application supplements, is being followed. Particular attention should be paid to the conditions under which intermediate product is shipped between the facilities, to ensure the integrity of the product.

iii. CONTRACT MANUFACTURING

A license holder is responsible for compliance with product and establishment standards, but may contract out part or all of the manufacturing to another facility. Establishments may hire contractors to perform many manufacturing operations, e.g., testing samples, filling and storing products. Both the manufacturer and contractor share responsibility for product quality; however, the manufacturer remains ultimately responsible. The contractor is responsible for complying with CGMPs, as applicable.

For establishments subject to the CGTP regulations in 21 CFR Part 1271 (e.g., HPC-C manufacturers), before entering into a contract, agreement, or other arrangement with another establishment to perform any step in manufacture, they must ensure that the establishment complies with applicable CGTP requirements. If, during the course of the contract, agreement, or other arrangement, they become aware of information suggesting that the establishment under contract, agreement, or other arrangement may no longer be in compliance with such requirements, reasonable steps must be taken to ensure the establishment complies with those requirements. If it is determined that the establishment under contract, agreement, or other arrangement is not in compliance with those requirements, the contract, agreement, or other arrangement with the establishment must be terminated.

During the inspection, review a copy of the current contract(s) and determine: (1) extent of services provided; (2) each party's responsibility for the product or operations performed; (3) who prepared the SOPs used by the contractor, and (4) who performed product quality control tests. If inspecting a contract manufacturer, verify that the license holder is notified of any manufacturing deviations and any manufacturing changes for its licensed product(s). If inspecting the license holder, who is responsible for final release of the batch, verify that all records created by the contract manufacturer and associated with release of any given batch are available and have been approved.

2. Change Reporting: For further guidance see: Guidance for Industry: Changes to an Approved Application - Biological Products

Requirements that manufacturers notify FDA about all changes in the product, production process, quality controls, equipment, facilities, responsible personnel or labeling, from that in their approved license application are described in 21 CFR 601.12. Determine if process changes made since the approval of the application have been properly reported.If biological drug products are reprocessed or reworked, they must be reported in a supplement to CBER prior to distribution, unless the reprocessing or reworking was done according to a procedure previously approved by CBER. The type of notification is based on the potential risk of the change having an adverse effect on the identity, strength, quality, purity, or potency of the product as it may relate to the safety or effectiveness of the product.

Changes that have a minimal effect on the safety or effectiveness of a product may be implemented before being reported to CBER; however, manufacturers are required to include such changes in their annual reports to the agency.

Data relevant to changes reported in annual reports (e.g., validation data) must be made available during FDA inspections. When a change has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as it may relate to the safety or effectiveness of a product, a manufacturer must submit a license supplement describing the change. If FDA does not advise the manufacturer within 30 days of submission of the supplement that the change requires approval prior to distribution of the product (i.e., a Prior Approval Supplement), the manufacturer may distribute product manufactured using the change pending approval of the supplement. These supplements are referred to as CBE-30, or changes being effected in 30 days.

When a change has a substantial potential to adversely affect the identity, strength, quality, purity, or potency of the product as it may relate to the safety or effectiveness of the product being manufactured, which uses that change, cannot be distributed until FDA approves a prior approval supplement (PAS) describing the change.

If the firm has an FDA-approved comparability protocol in place for a particular change or set of changes, the firm may be able to report the change in a lower reporting category that would be set forth in the approved comparability protocol supplement, if it follows the protocol when implementing the change.

For example, if a change would normally be reported as a prior approval supplement, the firm could report it in a CBE-30 supplement, if they have an approved comparability protocol for that change that sets forth a reduced reporting category, and the protocol was followed when making and evaluating the change.

When evaluating changes to an approved application:

Note: Manufacturer's annual reports are submitted based on the specific product approval date, indicated in 21 CFR 601.12(d). Therefore, the annual reporting time varies for any given product or company.

3. Components

Manufacturers who purchase components from outside sources are required to establish adequate specifications for such components. The licensed manufacturer is ultimately responsible for ensuring that components it uses conform to specifications and are acceptable for use. This may be done through inspections, sampling and testing, and/or through certificates of analysis from the supplier. The manufacturer should establish the validity of the certificates through experience, historical data, testing, and/or audits of the supplier.

For components received from outside sources, either purchased or otherwise received, verify that: (1) the firm has written, approved specifications for the component(s); (2) the firm evaluates and selects suppliers based on their ability to meet specified requirements, and (3) the type and extent of control needed over the component and suppliers has been defined and is based on the manufacturer's evaluation of the supplier.

Animal source material must meet the applicable requirements of 21 CFR 600.11. Investigators should determine if tests and specifications for materials of animal source that may potentially be contaminated with adventitious agents (e.g., mycoplasma, Bovine Spongiform Encephalopathy for bovine-derived products, and others) are performed as described in the license application.

Acceptance activities must be documented. Verify that the manufacturer has defined methods, e.g., inspections, tests, and other verification tools (certificates of analysis and/or supplier audits), to ensure that components conform to all specifications prior to release for use in manufacturing and that acceptance activities are documented in the batch record. Review the manufacturing SOPs and batch records for a representative number of lots to ensure that acceptance criteria are met for all components.

The firm should have well-established acceptance criteria for all materials. If buffers or media are prepared prior to use, determine if the firm has established and validated holding times and conditions, and has records to show the conditions are met.

Determine if the firm has adequate written specifications and procedures describing the receipt, handling, sampling, and storage of containers and closures, especially those that need to be sterile and/or pyrogen-free. Container closures should be made from material that will not hasten the deterioration of the product and should be free of surface contaminants and leachables.

4. Validation:

Validation data for the manufacturing process are generally reviewed during application review, as are the validation data to support changes that are reported in prior approval supplements. Determine if any changes in the process made since the approval of the application, for which a supplement is not required, have been validated in accordance with a protocol, and that the validation process is adequately documented.

If the firm uses computer systems to control any part of the process, determine if the software for computers and automated data processing systems are validated. If the firm is using a computerized record-keeping system, ensure the integrity of records is maintained. The systems should be such that records cannot be overwritten to disguise failing results. Document any computer systems the firm uses for control of the manufacturing process.

Determine if shipping conditions have been validated, including containers and methods. If the firm has contract manufacturers that perform some or all of the manufacturing steps, verify that shipping conditions for the partially processed materials have been validated, and the validated processes are followed and documented. The shipper must verify the product is maintained at the proper temperature during shipment, and must have records to demonstrate this.

5. Lot Release

Per 21 CFR 610.2(a), a manufacturer may be required to send samples of any lot of any licensed biological product, together with protocols showing results of applicable tests to CBER. It further states that upon notification by the Director, CBER, a manufacturer shall not distribute a lot of a product until the Director releases it.

Some manufacturers of well-established biological drug products have, through approved license supplements; been granted the alternative to lot release and are on a "Surveillance" program. Manufacturers on surveillance are still required to submit samples and/or protocols to CBER at specified intervals, but they may distribute the applicable products without receiving prior CBER lot release. Such manufacturers must still complete their own internal lot release process whether on CBER lot release or on a surveillance program.

The Director, CBER, at any time, including as a result of compliance history or regulatory actions, may remove a product from surveillance and return it to CBER lot release.

Review representative lot release test records to verify all specifications have been met. Compare raw test data against test results provided in protocols submitted to CBER to determine if they correlate. Check whether any lot has failed to be released, and if so, the reason for the failure and the disposition of all failed lots.

6. Biologic Product Deviations (BPDs): For further guidance see: Biological Product Deviation Guidances & Rules

Under 21 CFR 600.14, a manufacturer must report any event associated with the manufacturing, including testing, processing, packing, labeling, or storage, or with the holding or distribution of a licensed biological product, which may affect the safety, purity, or potency of a distributed licensed product.

BPDs are required to be reported to the CBER/OCBQ/DIS as soon as possible, but no later than 45 calendar days from the date of discovery of information reasonably suggesting a reportable event has occurred. Under 21 CFR 600.14, the manufacturer who holds the biologics license and who had control over the product when the deviation or unexpected event occurred must report a BPD.

If a manufacturer contracts out any manufacturing step, that manufacturing step is performed under the manufacturer's control under the regulation. Thus, under 21 CFR 600.14(a), the manufacturer must establish a procedure for receiving information from that contract manufacturing facility on all deviations, complaints, and adverse events that may affect the product.

A contract manufacturer (i.e., performs, under contract, a step in manufacturing for another facility) must conduct manufacturing in accordance with all applicable regulations. CBER provides ORA with direct access to BPD information through CEARS (CBER Error and Accident Reporting System). CEARS only captures the reportable events. Instructions for accessing the system are found on the CEARS intranet web page.

To facilitate industry reporting of BPD, CBER developed a standardized reporting format (FDA Form 3486) with both hard copy and electronic reporting. CBER encourages electronic reporting.

Prior to conducting an inspection, investigators should review the manufacturer's BPD submissions in CEARS. An assessment of the deviation codes may assist you in determining the optional system to inspect. Otherwise, select a representative sample of reports to verify the adequacy of the firm's corrective action.

7. Reporting of Adverse Experiences

Under 21 CFR 600.80, any life-threatening adverse experience, serious adverse experience, and unexpected adverse experience associated with the use of a biological product in humans, whether or not considered product related, must be reported by the manufacturer to CBER as soon as possible and no later than 15 days of initial receipt of information, and periodically, depending on the seriousness of the adverse reaction. Manufacturers of blood products, including plasma derivatives, are required to submit monthly reports for adverse experiences involving transmission of infectious diseases. Review records of adverse events received by the manufacturer, and determine if reports have been submitted to CBER as required. Contact OCBQ/DIS if there are questions or concerns regarding the reportability of an adverse experience.

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F. REPORTING

Note: If, at any time during the inspection, it is determined that a potentially serious health hazard exists, investigators and compliance officers should contact CBER's OCBQ/DCM immediately.

"Potential problems" should have a reasonable likelihood of occurring based upon observed conditions, records or events. Do not cite on the FDA 483 deviations from draft or proposed regulations or from guidance documents. Present verifiable evidence for conclusions of observed non-compliance with CGMPs. Investigators should not use the term "inadequate" without explaining why or how it is inadequate. Refer to policy in the IOM, Chapter 5, Section 5.2.3.14 and Field Management Directive 120 for further guidance on the content of Inspectional Observations.

The most critical observations should be listed first. Deficiencies that were noted during a previous inspection and remain uncorrected should be included on the FDA 483 as repeat deficiencies. Discuss with manufacturer prior observed deficiencies that have gone uncorrected.

If necessary, contact the ORA/OE CO to discuss and resolve questions relating to the possible inclusion of observations on the FDA 483. Good judgment is necessary when deciding whether conditions are objectionable in view of their relation to other conditions or controls at the given time and place. When there is continued uncertainty about the significance of one or more observations, they should not be listed on the FDA 483. They should, however, be discussed with the firm's management, and reported in the EIR.

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PART IVANALYTICAL

NO FIELD ANALYSES ARE PLANNED UNDER THIS PROGRAM.

PART IV - ANALYTICAL

NO FIELD ANALYSES ARE PLANNED UNDER THIS PROGRAM.

The routine collection and analysis of physical samples is not envisioned under this program. If CBER requests sample collection, specific instructions will be provided. Consult with CBER program contacts identified in Part VI, before collecting samples for agency analysis, except for documentary samples for interstate commerce (collect a documentary sample in accordance with IOM 4.4.6.2.1 to support regulatory/administrative action).

Contact the CBER Sample Custodian (301-594-6517) before shipping any samples to CBER. No one is available to receive samples over the weekend. All samples collected under this program will be shipped to:

Center for Biologics Evaluation and Research
Attention: Sample Custodian, HFM-672
5516 Nicholson Lane, Building B, Room 113
Kensington, MD 20895

Collect any samples of a potentially bio-hazardous nature in accordance with IOM 1.5.

Original results of analyses will be forwarded to the ORA/OE CO, with a copy to the home district of the involved facility. Investigators should document in FACTS to whom CBER should send the sample results. If unable to document in FACTS, then use Form FDA 464a, C/R Continuation Sheet.

Copies of collection reports for physical samples must be submitted to CBER/OCBQ/DCM, HFM-610.

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PART V - REGULATORY/ADMINISTRATIVE STRATEGY

The evaluation of inspection findings and any resultant recommendation for enforcement action will be conducted in accordance with existing procedures and the RPM. The Team Biologics lead investigator will ensure the home district will be advised of inspectional and compliance activities related to facilities located within the district.

The decision on the type of action to recommend should be based on the seriousness of the documented deficiencies, and the most effective way to protect the public health. Because the number of manufacturers of biological drug products (vaccines, allergens, etc.) is often small, medical need and relative availability of the product(s), as well as the potential adverse effect of the CGMP deficiencies on the finished product(s) should be considered when determining the appropriate advisory, administrative or judicial action.

A firm's written corrective action, in response to the FDA 483, should not preclude the consideration of an advisory, administrative, or judicial action. If the objectionable observations represent a continuing pattern of non-compliance, a failure to correct significant deficiencies noted during a previous inspection, or the deficiencies pose a serious threat to the public health, and voluntary action is either not appropriate or can not be readily accomplished, the appropriate advisory, administrative, or judicial action should be recommended.

State of Control

A firm is considered to be operating in a state-of-control when it employs conditions and practices that ensure compliance with the intent of Section 501(a)(2)(B) of the Act, and the portions of the CGMP regulations that pertain to their systems. A firm in a state of control produces finished biological drug products for which there is an adequate level of assurance of quality, strength, identity, purity, and potency.

Well-documented CGMP deficiencies provide the evidence for concluding that a firm is not operating in a state of control. Evidence of serious deficiencies within a system could constitute overall failure of that system, and the firm to be considered not in a state-of-control. When the inspectional findings demonstrate that a firm is not operating in a state of control, and/or the establishment's management is either unwilling or unable to implement full corrections in a timely manner, administrative or judicial action should be considered.

Regulatory recommendations should be based on serious deficiencies that are well documented with supporting evidence. The quality of any action begins with the quality of evidence collected at the time of the inspection, to support the observed objectionable conditions. The recognition, collection, and effective presentation of evidence are essential to any successful advisory, administrative, or judicial action. Establish individual responsibility, and identify persons to hold accountable for violations and with whom the agency should communicate to seek lasting corrections, and/or to be the subject of enforcement actions.

Refer to the RPM to determine the appropriate advisory, administrative or judicial action based on the inspectional findings. Early consultation with CBER/OCBQ/DCM is critical when immediate action is indicated, e.g., license suspension, a temporary restraining order (TRO), etc. See RPM Chapter 6 regarding an injunction to protect the public health.

When inspectional findings indicate the potential for fraud, e.g., falsification, counterfeiting, illegal importation, and/or drug diversion, the investigator should notify the Team Biologics Compliance Officer, the Team Biologics Supervisor, and OCBQ/DCM (HFM-610), who will alert the appropriate OCI office. The investigator should continue to pursue any public health concerns, in coordination with CBER/OCBQ, concurrently.

An initial decision on the type of action to recommend should be consistent with the RPM and be based on the seriousness and frequency of the deficiencies as well as the firm's overall compliance history. For example, classify an inspection report that documents one or more systems not in a state-of-control as OAI, and consider recommending a Warning Letter or taking other appropriate action.

For a licensed biologic, the advisory, administrative, and judicial options available include:

Deficiencies

The investigator should verify through actual observation, whenever possible, whether or not the firm adheres to the applicable regulations and the law. The following, although not all- inclusive, are examples of deficiencies that may be indicative of the firm's state-of-control. Inspectional findings that demonstrate a firm is not operating in a state-of-control may be used as evidence for taking appropriate advisory, administrative, or judicial actions.

Examples of deficiencies are arranged by System. Any deficiency listed in one system may be applicable to other systems. For example, deficiencies pertaining to the training and qualification of employees, or deficiencies involving discrepancy and failure investigations, are listed only under the Quality System. However, both deficiencies could be applicable to multiple systems. In addition, while the CGMP regulations apply to the manufacture of biological drug products, the same CGMP principles apply for the manufacture of biological intermediates and drug substances under Section 501(a)(2)(b) of the FD&C Act, and the Biologics regulations under 21 CFR Part 600.

Quality System

Firms must have an effective quality assurance program, and should not rely solely on finished product testing to ensure products meet their specifications. The responsibilities and functions of the quality control unit must be clearly defined. QA is not limited to processing and finished products, but incorporates all the major systems, e.g., components and in-process materials, facilities and equipment, complaint handling, failure investigation, and change control.

NOTE: Consult with CBER/DIS before including observations on the Form FDA 483, or in an enforcement action recommendation, that are related to non-conformity with commitments made in the Biologics License Application.

Facilities and Equipment System

Deficiencies in this system may include violative conditions relating to the design, maintenance and cleaning of the facility and equipment, including but not limited to air handling and water systems, lighting, and sanitation.

FACILITIES:

EQUIPMENT:

Materials System

Deficiencies in this system may include violative conditions relating to material handling, including, but not limited to, in-process materials and finished product examination, sampling, testing, quarantine, storage, issuance of materials, including containers and closures, and discrepancy investigation and appropriate follow-up.

Production System

Deficiencies in this system may include violative conditions relating to production activities including, but not limited to, batch processing and control records, reprocessing, in process controls, tests and examinations, equipment cleaning and use logs.

Packaging and Labeling System

Deficiencies in this system may include violative conditions relating to packaging operations, and the handling of labels and labeling including, but not limited to, the receipt, inspection, issuance, and reconciliation of labels, and discrepancy investigation and follow-up

Laboratory Control System

Deficiencies in this system may include violative conditions relating to laboratory functions including, but not limited to, staffing, facilities, calibration and maintenance of equipment, specifications and standards, sampling plans and testing methodology.

Donor Eligibility System

Deficiencies in this system may include violative conditions relating to donor eligibility including, but not limited to, donor screening, donor testing, quarantine of products before completion of the donor eligibility determination, storage of products from ineligible donors, and use of products in cases of urgent medical need.

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PART VI - REFERENCES AND PROGRAM CONTACTS

A. REFERENCES:

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B. PROGRAM CONTACTS:

CBER

For questions regarding CBER policy or requests for assistance: OCBQ, HFM-600

Gilliam B. Conley, Director
301-827-6220, FAX: 301-827-6748
Gilliam.Conley@fda.hhs.gov

Janet Ishimoto, Chief
301-827-6220
Janet.Ishimoto@fda.hhs.gov

Damaris Lopez-Rosario, Team Biologics Liaison
301-827-6353
Damaris.Lopez-Rosario@fda.hhs.gov

Sharon OCallaghan, OCBQ/DIS/PSB, 301-827-6346
Sharon.Ocallaghan@fda.hhs.gov

Beth Rogerson, OCBQ/DIS/PSB, 301-827-6349
Susan.Rogerson@fda.hhs.gov

Diane Alexander, Chief, Biological Drug and Device Compliance Branch
301-827-6201, FAX 301-594-0940
diane.alexander@fda.hhs.gov

License Denials, Debarment, Civil Money Penalties, Application Integrity, Biological Product Recalls, License Suspensions, Revocations and Denials Warning Letters, Seizures, Injunctions, Citations, Prosecutions, Import/Export Programs, Compliance Status Checks, Certificates of Export, Advertising and Promotional Labeling

Mailing Address for CBER Contacts:

Food & Drug Administration
Center for Biologics Evaluation and Research
Office of Compliance & Biologics Quality
Division of Inspections and Surveillance, HFM-650
1401 Rockville Pike
Suite 200N
Rockville, MD 20852-1448

301-594-6517

Center for Biologics Evaluation and Research
Attention: Sample Custodian, HFM-672
5516 Nicholson Lane, Building B, Room 113
Kensington, MD 20895

ORA/ORO

For questions regarding inspection policy or requests for guidance, and Team Biologics contact:

David Glasgow, HFC-130, 301-827-4312
Director, Division of Domestic Field Operations
david.glasgow@fda.hhs.gov

Team Biologics Supervisor, HFC-130
Division of Domestic Field Operations

Office of Enforcement

For questions pertaining to recalls:

Recall Operations Staff
Division of Compliance Management and Operations, HFC-210
Office of Enforcement
240-632-6856
FAX 240-632-6859

Armando Zamora
240-632-6855
armando.zamora@fda.hhs.gov

Cecilia Wolyniak
240-632-6867
cecilia.wolyniak@fda.hhs.gov

For questions regarding compliance policy issues:

Division of Compliance Management and Operations, HFC-210
240-632-6850
FAX 240-632-6859

Robert Hummel, HFC-230
240-632-6845OE/DCP
robert.hummel@fda.hhs.gov

Jacqueline Little, Ph.D. HFC-210
240-632-6863
OE/DCMO
jacqueline.little@fda.hhs.gov

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PART VIICOORDINATION AND PROGRAM MONITORING

CBER/OCBQ/DIS will work cooperatively with ORA, the Biological Products Field Committee, and the Team Biologics Operations Group to monitor the inspectional and compliance accomplishments under this compliance program, and the status of the inspected industry establishments.

The ORA annual workplan, developed by CBER and ORA, provides overall resource allocations and anticipated numbers of inspections. However, current industry practices encountered during an inspection, the past compliance history of establishments, or other compliance developments, may necessarily result in unplanned inspections or in individual CGMP inspections taking more or less time than estimated in the workplan.

As is customary, ORA continues to have the primary responsibility for ensuring:

(1) That the program strategies, priorities, and procedures articulated in this compliance program are followed by the ORA staff, and
(2) Potential problems or needs for policy/program clarification are brought to the attention of CBER/OCBQ and the Team Biologics Operations Group.

CBER and ORA jointly coordinate activities to achieve industry compliance with applicable laws, regulations, and Court orders (e.g., Consent Decrees of Permanent Injunction).

CBER/OCBQ will continue to use accomplishment data from the ORA Field Accomplishment and Compliance Tracking System (FACTS), administrative or judicial action recommendations, requests for policy decisions/clarification received from the public or the industry, and input from CBER scientific and product experts to provide overall direction to FDA's CGMP initiatives, which are supported by this risk-based strategic compliance program.

The Team Biologics Operations Group conducts periodic conference calls and/or meetings with participation by ORA and CBER units.

CBER/OCBQ/DIS provides appropriate background material, including license and lot release information, and copies of applicable CBER correspondence and reports, to the Team Biologics investigators prior to scheduled inspections.

CBER/OCBQ will carefully evaluate the experience with this systems-based inspection program through inspection reports and other compliance data to determine its effectiveness and to continually assess and improve the quality of the CBER products inspection program. It also will carefully review industry compliance, product developments within industry, and the safety and quality of CBER-regulated biological drug products will likewise be closely monitored.

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ATTACHMENTS - Product Guidance

ATTACHMENT 1: FRACTIONATORS
ATTACHMENT 2: VACCINES
ATTACHMENT 3: RECOMBINANT PRODUCTS
ATTACHMENT 4: ALLERGENICS
* Flow Diagram
* Appendices to Flow Diagram
ATTACHMENT 5: MINIMALLY MANIPULATED, UNREALTED ALLOGENEIC UNBILICAL CORD BLOOD (HEMATOPOIETIC PROGENITOR CELLS, CORD [HPC-C])
ATTACHMENT 6: PRE-LICENSE AND PRE-APPROVAL INSPECTIONS

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ATTACHMENTS - Product Guidance

ATTACHMENT 1: FRACTIONATORS

Plasma Fractionation

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