Compliance Program Guidance Manual
Inspection of Biological Drug Products - 7345.848
| Implementation Date: December 1, 2004 | Completion Date: September 30, 2008 |
| Product Codes:
57CY [Viral and Rickettsial Vaccines] |
Programs/Assignment Codes:
45848A Pre-License Inspection -Allergenics |
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 405.02 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 145.
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 designate on the FDA-464, Collection Report, to whom the sample results should be forwarded.
Copies of collection reports for physical samples must be submitted to CBER/OCBQ/DCM, HFM-610.
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 Core Team 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 C GMP 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 Core Team Leader, 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:
| Action | Among other things, consider if, |
|---|---|
| Warning Letter: | Violations of regulatory significance that cause one or more systems to be considered not in a state-of-control. |
| License Revocation (21 CFR 601.5) |
Notice of Intent to Revoke with Opportunity for Correction: Unable to gain access to the manufacturing facility for inspection Licensed products are not safe or effective for their intended use, or are misbranded with respect to any such use. Manufacturer fails to report a change in accordance with 21 CFR 601.12 Manufacturer fails to conform to applicable standards to ensure product safety, potency and purity Licensed products are no longer manufactured Direct Revocation without Opportunity for Correction: |
| License Suspension (21 CFR 601.6) |
Reasonable grounds for revocation and a danger to health exist. It provides immediate withdrawal of the authorization to ship a biological product in interstate commerce. |
| Seizure | Manufacturer is unwilling or unable to retrieve violative products, or products held for sale are unsuitable for safe use. U.S. Marshal takes possession of products through Court Order pursuant to Section 304 of the Federal Food, Drug, and Cosmetic Act. |
| Injunction | A current health hazard exists, the establishment has a history of uncorrected violations despite previous warnings, suspension of the firm's license would result in an unacceptable shortage of products, and/or to halt intrastate distribution of products manufactured under violative conditions |
| Prosecution | Fraud, gross, flagrant or intentional violations, health hazards, or serious violations that have not been corrected. |
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.
- Training/qualification of employees
- Employees [are/were] not trained in the particular operation that they performed and/or in CGMPs related to their job functions. 211.25(a)
- Individuals engaged in the manufacture, processing, and packing of products [do/did] not have education, training, and experience, or any combination thereof, to enable them to perform assigned functions. 211.25(b), 600.10(b)
- There [are/were] not an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each product. 211.25(c)
- Product reviews by the quality control unit, at least annually
- The quality control unit [fails(ed)] to review production records to assure that no errors has occurred, or if errors have occurred that they are fully investigated. 211.22(a)
- The quality control unit [fails(ed)] to conduct and/or document an annual review of production records so that data therein can be used for evaluating the quality standards of each product to determine the need for changes in product specifications, manufacturing and/or control procedures. 211.180(e)
- Written procedures for production and process control [are/were] not drafted, reviewed and approved by the appropriate organizational units and/or the quality control unit. 211.100(a)
- Complaint reviews; documented, evaluated, and investigated including corrective action and follow-up where appropriate
- Written procedures [are/were] not established and/or followed for the annual review and evaluation of complaints and investigations. 211.180(e)(2)
- Written procedures [fail(ed)] to include provisions for review by the quality control unit of complaints involving the possible failure of the product to meet any of its specifications and, a determination as to the need for an investigation. 211.198(a)
- The compliant investigation [does/did] not include documentation of the findings and/or follow-up. 211.198(b)(2)
- Discrepancy and failure investigations related to manufacturing and testing; documented, evaluated, and thoroughly investigated, including corrective actions and follow-up where appropriate
- Failure to conduct investigations into unexplained discrepancies or
- The failure of a batch or any of its components to meet specifications whether or not the batch was distributed.
- [Are/were] not always documented
- [Do/did] not always include the conclusions and/or follow-up
- [Do/did] not always extend to other batches of the product
- [Do/did] not always extend to other products with the associated discrepancies 211.192
- Adherence to an adequate Out of Specification (OOS) procedure
- Deviations from the written procedures [are/were] not recorded and/or justified. 211.160(a)
- Failure to conduct investigations into unexplained discrepancies or the failure of a batch or any of its components to meet specifications: 211.192
- Change control procedures; documented, evaluated, approved, and the need for revalidation assessed by the quality control unit.
- The quality control unit [fails(ed)] to:
- Approve or reject all procedures and/or specifications impacting on the identity, strength, quality, and purity of the products. 211.22(c)
- Draft, review, and/or approve written procedures, including any changes. 211.100(a)
- Conduct and/or document an annual review of production records. 211.180(e)
- Reprocessing and/or reworking procedures; evaluated, reviewed and approved by the quality control unit, and the impact on validation and stability evaluated
- Written procedures [are/were] not established and/or followed for reprocessing batches of products, and [do/did] not include the steps to be taken to assure that the reprocessed batches conform to all established standards, specifications, and characteristics. 211.115(a)
- Reprocessing procedures [are/were] not performed with the review and approval of the quality control unit. 211.115(b), 601.12
- Returned and salvaged product; assessment and investigation conducted and expanded where warranted, including disposition
- Written procedures [are/were] not established to assure that the responsible officials of the firm are made aware of returned and/or salvaged product, and are notified in writing of any investigations conducted. 211.180(f)
- Product rejects investigated with corrective action where appropriate
- Failure to establish and/or follow written procedures for the receipt, identification, storage, handling, sampling, testing; and approval or rejection of components and product containers and closures. 211.80(a)
- Products that [fail(ed)] to meet established standards or specifications and any other relevant quality control criteria [are/were] not rejected. 211.165(f)
- Failure to conduct investigations into unexplained discrepancies or the failure of a batch or any of its components to meet specifications . 211.192
- Stability failures; investigation
- Failure to conduct investigations into unexplained discrepancies and/or the failure of a batch or any of its components to meet specifications. 211.192
- The quality control unit [fails(ed)] to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. 211.22(a)
- Quarantine products
- Failure to:
- Ensure that rejected components, product containers, and closures [are/were] identified and controlled under a quarantine system to prevent their use in manufacturing or processing operations for which they are unsuitable. 211.89
- Establish and/or follow written procedures that describe the warehousing of products, including quarantine before release. 211.42(a)
- Finished product distribution records by lot
- Failure to establish and/or implement a system by which the distribution of each lot of product could be readily determined to facilitate its recall if necessary. 211.150(b)
- Distribution records [do/did] not contain the name and strength of the product and description of the dosage form. 211.196
- Adverse Experience Reporting (AER)
- AERs [are/were] not submitted to CBER, and/or reviewed as required. 21 CFR 600.80
- Licensing
- Significant manufacturing changes [are/were] not reported and [are/were] implemented, and product [is/was] distributed prior to obtaining the required CBER approval. 601.12(b)
- Product [is/was] not manufactured as described in the approved license application. 601.2(d)
- Reporting of Biological Product Deviations (BPDs)
- Reportable BPDs [are/were] not submitted to CBER, or [are/were] not submitted within the required timeframe. 600.14
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.
FACILITES:
- Maintenance
- Buildings used in the manufacture, processing, packing, or holding of products [are/were] not maintained in a state of good repair. 211.58
- Facility design and air handling systems for prevention of cross-contamination (e.g., cytotoxics, live virus, spore forming organisms)
- Building(s) used in the manufacture, processing, packing, or holding of a product [are/were] not of suitable size, construction and/or location to facilitate cleaning, maintenance, and proper operations. 211.42(a)
- Operations [are/were] not performed within specifically defined areas of adequate size. 211.42(c)
- Floors, walls, and ceilings of aseptic processing areas are not smooth, hard surfaces that are easily cleanable. 211.42(c)(10)
- General air handling systems
- Adequate ventilation [is/was] not provided. 211.46(a)
- Equipment for adequate control over air pressure, microorganisms, dust, humidity, and temperature [are/were] not provided. 211.46(b), 600.11(a)
- Air filtration systems, [are/were] not used, when appropriate, on air supplies to production areas. 211.46(c)
- Specifically designed area for the manufacturing operations performed by the firm to prevent contamination or mix-ups
- Buildings [do/did] not have adequate space for the orderly placement of equipment and materials to prevent mix-ups and/or contamination between different components, product containers, closures, labeling, in-process materials, and/or products. 211.42(b)
- There [are/were] not separate or defined areas or other control systems for the firm's operations as necessary to prevent contamination or mix-ups, including:
- Receipt, identification, storage, and withholding from use of components, product containers, closures, and labeling pending sampling, testing, or examination by the quality control unit before release for manufacturing or packaging
- Holding of rejected, and storage of released components, product containers, closures, and labeling before disposition
- Storage of in-process materials
- Manufacturing and processing operations
- Quarantine storage before release of products
- Control and laboratory operations
- Aseptic processing, including:
- An environmental monitoring system
- A room and equipment cleaning/disinfecting system
- A maintenance system for equipment used to maintain aseptic conditions. 211.42(c)
- Laboratory and bleeding rooms used for the processing of products [are/were] not effectively fly-proofed and kept free of flies and vermin. Rooms [are/were] not constructed as to assure the freedom from dust, smoke, and other deleterious substances and to permit thorough cleaning and disinfection. 600.11(c)
- Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents
- Buildings used in the manufacture of products [are/were] not:
- Maintained in a clean and sanitary condition. 211.56(a)
- Free of infestation by rodents, birds, insects, and other vermin. 211.56(a)
- Written sanitation procedures:
- [Are/were] not established for the use of suitable rodenticides, insecticides, fungicides, and fumigating agents. 211.56(c)
- [Are/were] not designed to prevent the contamination of equipment, components, product containers, closures, packaging, labeling materials, or products. 211.56(c)
EQUIPMENT:
- Adequacy of equipment design, size, and location
- Equipment used in the manufacture of the product [is/was] not of appropriate design, adequate size, and/or suitably located for its intended use and/or for its cleaning and maintenance. 211.63
- Equipment surfaces should not be reactive, additive, or absorptive
- Equipment is constructed so that surfaces that contact components, in-process materials, or products are reactive, additive, and/or absorptive and may alter the safety, identity, strength, quality, or purity of the product. 211.65(a)
- Appropriate use of substances required for equipment operations (lubricants, coolants, refrigerants, etc.) contacting products/containers/etc.
- Equipment is constructed so that substances required for operation, such as lubricants or coolants, come into contact with components, product containers, closures, in-process materials, or products and may alter the safety, identity, strength, quality, or purity of the product. 211.65(b)
- Equipment cleaning and use logs
- A written record of major equipment cleaning, maintenance, and use [is/was] not included in individual equipment logs that show the date, time, product, and/or lot number of each batch processed. 211.182
- Cleaning procedures and cleaning validation
- Written procedures for cleaning and maintenance of equipment, including utensils, used in the manufacture of the product [are/were] not established and/or followed. 211.67(b)
- Equipment and/or utensils [are/were] not cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the product. 211.67(a)
- Records of equipment maintenance, cleaning, sanitizing, and inspection [are/were] not kept. 211.67(c)
- Equipment qualification, calibration and maintenance, including computer qualification/validation and security
- Equipment [is/was] not routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of calibration checks and inspections [are/were] not maintained. 211.68(a)
- Appropriate controls [are/were] not exercised over computer or related systems to assure that only authorized personnel institute changes in master production and control records or other records. 211.68(b)
- Input to and output from the computer or related system of formulas or other records or data [are/were] not checked for accuracy. 211.68(b
- Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss are not maintained. 211.68(b)
- Equipment identification practices (where appropriate)
- Major equipment used during the production [is/was] not properly identified. 211.105(a)
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.
- Identification, Inventory and Storage of components, containers, closures
- Written procedures [are/were] not established, and/or followed for the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and product containers and closures. 211.80(a)
- Each lot of product containers [is/was] not identified with a distinctive code or status (e.g., quarantined, approved, or rejected ). 211.80(d)
- The components, product containers and/or closures [are/were] not handled and/or stored in a manner to prevent contamination. 211.80(b)
- Storage under quarantine until tested or examined, and released
- The components, product containers, and/or closures [are/were] not stored under quarantine until they were released. 211.82(b)
- The product containers and/or closures [are/were] not withheld from use, and/or were released for use by the quality control unit before the lots had been sampled and tested by the quality control unit. 211.84(a)
- Representative samples collected, tested or examined using appropriate means
- A representative sample of each shipment of each lot of components [is/was] not collected for testing or examination. 211.84(b)
- At least one specific identity test is conducted on each lot of each component
- Tests [are/were] not conducted to verify the identity of each component of a product. 211.84(d)(1)
- A visual identification is conducted on each lot of containers and closures
- The product containers and/or closures [are/were] not examined visually for container damage or broken seals upon receipt or before acceptance. 211.82(a)
- Testing or validation of supplier's test results for components, containers and closures
- Written specifications for each component [does/did] not include:
- Testing for conformity with all appropriate written specifications
- In lieu of such testing, a report of analysis from the supplier of the component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals. 211.84(d)(2)
- Written specifications for each container and closure [does/did] not include:
- Testing for conformity with all appropriate written procedures
- In lieu of such testing, a certificate of testing from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier's test results through appropriate validation of the supplier's test results at appropriate intervals . 211.84(d)(3)
- The written procedures for examination and testing components [does/did] not include established specifications for contamination. 211.84(d)(5)
- Rejection of any component, container, closure not meeting acceptance requirements
- Failure to reject lots of material that did not meet specifications. 211.84(e)
- Appropriate retesting/reexamination of components, containers, closures
- After prolonged storage in an uncontrolled area, the product containers and/or closures were not retested or reexamined and approved by the quality control unit. 211.87
- Quarantine of rejected materials
- Failure to assure that rejected components, product containers, and/or closures [are/were] identified and controlled under a quarantine system designed to prevent their use in operations for which they are unsuitable. 211.89
- Water and process gas supply, design, maintenance, validation and operation.
- The written specifications for each component [does/did] not include:
- Testing for conformity with all appropriate written specifications
- In lieu of such testing, a report of analysis from the supplier of the component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals. 211.84(d)(2)
- Containers and closures:
- The product containers and/or closures could not be shown to be non reactive, additive, or absorptive. 211.94(a)
- Standards or specifications, methods of testing, and methods of cleaning, sterilizing, and processing to remove pyrogenic properties [are/were] not written and/or followed for product containers and closures. 211.94(d)
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.
- Written procedures; deficiencies
- Written procedures for production and process controls [does/did] not assure that products have the identity, strength, quality, and purity they purport or are represented to possess. 211.100(a)
- Deviations from the written procedures [are/were] not recorded and justified. 211.100(b)
- Adequate procedure for charge-in of components
- Procedures for charge-in of components [do/did] not include:
- Written production and control procedures designed to assure that the products produced, have the identity, strength, quality, and purity they purport or are represented to possess. 211.101
- Formulation of the batch to provide not less than 100 percent of the labeled or established amount of active ingredient. 211.101(a)
- Adequate supervision of component weighing and measuring operations. 211.101(c)
- Identification of equipment with contents, and where appropriate phase of manufacturing and/or status
- All compounding and storage containers, processing lines, and major equipment used during the production of a batch of product [are/were] not properly identified at all times to indicate their contents or, when necessary, their phase of processing of the batch. 211.105(a)
- Calculation and documentation of actual yields and percentage of theoretical yields
- Actual yields and percentages of theoretical yield [are/were] not determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the product. 211.103
- Batch production and control records
- Batch production and control records are/were not prepared for each batch of product and/or [do/did] not include complete information relating to the production and control of each batch. 211.188, 600.12(a)
- Established time limits for completion of phases of production
- Time limits for the completion of each phase of production, to assure the quality of the product, [has/have] not been established. 211.111
- Implementation and documentation of in-process controls, tests, and examinations
- Written procedures that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch [are/were] not established and/or followed. 211.110(a)
- Justification and consistency of in-process specifications and product final specifications
- In-process specifications [are/were] not consistent with product final specifications. 211.110(b)
- Prevention of objectionable microorganisms in sterile products
- Appropriate written procedures, including validation of any sterilization process, designed to prevent microbiological contamination of products purporting to be sterile, [are/were] not established and/or followed. 211.113(b), 600.11(b)
- Adherence to preprocessing procedures (e.g., set-up, line clearance, etc.)
- Production and process control procedures [are/were] not: 211.100(b)
- Written and/or followed for various production and process control functions
- Documented at the time of performance
- Deviations from the written procedures [are/were] not recorded and justified.
- Master production and control records
- Master production and control records [do/did] not include: 211.186
- Complete manufacturing and control instructions
- Sampling and testing procedures
- Specifications
- Special notations and/or precautions to be followed
- Written procedures for preparing the master production and control records
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
- Acceptance operations for packaging and labeling materials; examination, storage and usage
- The procedures describing the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials [are/were] not written and/or followed. 211.122(a)
- Labeling and packaging materials [are/were] not representatively sampled, examined and/or tested upon receipt and before use in packaging or labeling of product. 211.122(a)
- Labeling and/or packaging materials not meeting appropriate written specifications [are/were] approved and released for use. 211.122(b)
- Labels and other labeling materials for each different product, strength, dosage form, or quantity of contents [are/were] not stored separately and/or suitably identified. 211.122(d)
- Printing devices on/or associated with, manufacturing lines used to imprint labeling upon the product unit label or case are/were not monitored to assure that all imprinting conforms to the print specified in the batch production record. 211.122(h)
- Control of issuance of labeling, examination of issued labels and reconciliation of used labels
- Labeling issued for use in product labeling operations:
- [Are/were] not strictly controlled 211.125(a)
- [Are/were] not carefully examined for identity and conformity to the labeling specified in the master or batch production records. 211.125(b)
- The quantities of labeling issued, used, and returned are not reconciled, and/or discrepancies between the quantity of finished product and the quantity of labeling issued [are/were] not evaluated. 211.125(c)
- There is no assurance that all excess labeling bearing lot or control numbers [is/was] destroyed . 211.125(d)
- Packaging and labeling operations, line clearance, inspection and documentation including validation and security of computerized processes
- Written procedures [are/were] not established, and/or not followed, and/or procedures do not assure that correct labels, labeling, and packaging materials are used. 211.130
- Physical or spatial separation [is/was] not adequate to prevent mix-ups and/or cross-contamination from operations on other products. 211.130(a)
- Filled unlabeled product containers that are set aside and held for future labeling operations [are/were] not identified and/or handled to preclude mislabeling of individual containers, lots, or portions of lots. 211.130(b)
- Products [are/were] not identified with a lot or control number that permits determination of the history of the manufacture and control of the batch. 211.130(c)
- Packaging and labeling facilities [are/were] not inspected immediately before use to assure that all products and packaging and labeling materials not suitable for subsequent operations [are/were] removed. 211.130(e)
- Equipment used in computerized packaging and/or labeling processes [are/were] not routinely calibrated, inspected or checked according to a written program designed to assure proper performance. 211.68(a)
- Changes in the computers and related systems [are/were] not appropriately controlled to assure only authorized personnel performed them. 211.68(b)
- Control of filled unlabeled containers, later labeled under multiple private labels
- There [are/were] no written procedures for the identification and handling of filled product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots..211.130(b)
- Expiration dating
- The product labels: [ 211.137(a), (d)]
- [Do/did] not bear an expiration date determined by appropriate stability testing
- Have expiration dates that [are/were] not related to storage conditions on the label
- [Do/did] not bear expiration dates for both the reconstituted and lyophilized product
- Examination of the labeled finished product [211.134(a), (b)]
- Labeled finished products,
- [Are/were] not examined during the finishing operations to provide assurance those containers and packages in the lot have the correct label
- [Are/were] not sampled with a representative number of units for visual examination for correct labeling at the completion of finishing operations
- [Do/did] not include documentation of examination operations
- Complete labeling control records, including specimens or copies of all labeling used
- Records [are/were] not maintained for each shipment of each different labeling and packaging material indicating receipt, examination or testing. 211.122(c)
- Records documenting the examination and review of labels and labeling for conformity with established specifications [are/were] not maintained. 211.184(d)
- Batch production and control records [do/did] not include complete labeling control records including specimens or copies of all labeling used. 211.188(b)(8)
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.
- Written procedures and control system for laboratory operations
- Specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, including any changes, [are/were] not drafted by the appropriate organizational unit and/or reviewed and approved by the quality control unit. 211.160(a)
- Calibration and maintenance programs for analytical instruments and equipment
- There [are/were] no written procedures, or procedures are not followed for the calibration of instruments, apparatus, gauges, and recording devices at suitable intervals containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. 211.160(b)(4)
- Adherence, validation/verification to the written methods of analysis
- There [are/were] no written procedures describing method of sampling and the number of units per batch to be tested. 211.165(c)
- The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm [are/were] not established and/or documented. 211.165(e)
- Testing and release for distribution
- Laboratory testing [does/did] not determine conformance to final specifications, including identity and strength of each active ingredient, prior to release of each batch of product 211.165(a)
- Appropriate laboratory testing [is/was] not performed for each batch of product required to be free of objectionable microorganisms. 211.165(b)
- Specifications, standards, and representative sampling plans
- Laboratory controls [do/did] not include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure components and products conform to appropriate standards of identity, strength, quality and purity. 211.160(b)
- Stability testing program, including demonstration of stability indicating capability of the test methods
- The written testing program designed to assess the stability characteristics of products [do/did] not include:
- The sample size and test intervals for each attribute tested
- Storage conditions for samples retained for testing 211.166
- Special testing requirements
- Failure to conduct appropriate laboratory testing for each batch of drug product purporting to be sterile and/or pyrogen-free 211.167(a)
- Adequate reserve samples; documentation of reserve sample examination
- An appropriately identified reserve sample(s), of adequate number, representative of each lot or batch of product [is/was] not retained and/or stored under conditions consistent with product labeling and/or in the same immediate container-closure system.
- Reserve samples [are/were] not examined visually at least once a year for evidence of deterioration. 211.170
- Required testing is performed on the correct samples
- In the determination of conformance to appropriate written specifications:
- The samples [are/were] not representative and/or adequately identified for each lot of components 211.160(b)(1)
- T he samples [are/were] not representative and/or adequately identified. 211.160(b)(2)
- The samples [are/were] not representative and/or adequately identified for the products. 211.160(b)(3)
- Laboratory records
- [Do/did] not include:
- A statement of each method used in the testing of the sample, indicating the location of data that establishes the methods used in the testing of the sample met proper standards of accuracy and reliability as applied to the product tested. 211.194(a)(2)
- A complete record of all data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays. 211.194
- A complete record of all data secured in the course of each test, including all graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, product container, closure, in- process material, or product, and lot tested. 211.194(a)(4)
- A record of all calculations performed in connection with the test, including units of measure, conversion factors, and equivalency factors. 211.194(a)(5)
PART VI - REFERENCES AND PROGRAM CONTACTS
- REFERENCES:
- Federal Food, Drug, and Cosmetic Act, and Related Laws.
- Public Health Service Act.
- Title 21, Code of Federal Regulations, Parts 11, 210, 211, 314, 600, 601, 606, 607, 610, 640, and 680.
- Compliance Program Guidance Manual, CP 7356.002, Drug Manufacturer Inspections; CP 7356.002A, Sterile Drug Process Inspections.
- Guidance on Alternatives to Lot Release for Licensed Biological Products, CBER, July 1993.
- Guidance to Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product, January 1999.
- Guideline on General Principles of Process Validation, 1987
- Compliance Policy Guide (CPG), Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08, Sec 490.100, March 2004.
- Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing - Good Manufacturing Practice, September 2004.
- Guide to Inspections of High Purity Water Systems, ORA/ORO, June 1993.
- Guide to Inspection of Pharmaceutical Quality Control Laboratories, July 1993.
- Guide to Inspection of Microbiological Pharmaceutical Quality Control Laboratories, July 1993.
- Guide to Inspection of Validation of Cleaning Processes, July 1993.
- Guide to Inspections of Lyophilization of Parenterals, ORA/ORA/DFI, July 1993.
- Points to Consider in the Manufacture of Recombinant DNA Derived Products, Monoclonal Based In Vitro and In Vivo Products, CBER.
- United States Pharmacopoeia, Current Revision and Supplements.
- International Conference on Harmonization Guideline; Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, November 1995.
- FDA Investigations Operations Manual, Sections 500-529, 560-565, 590-595, 635, 773, 921, 924, 927-928, 1026 and appendix B. http://www.fda.gov/ora/inspect_ref/iom/
- FDA Regulatory Procedures Manual (RPM), Chapter 4- Advisory Actions, Chapter 5 -Administrative Actions,Chapter 6 - Judicial Actions, Chapter 7- Recall and Emergency Procedures, Chapter 9 - Import Operations/Actions.
http://www.fda.gov/ora/compliance_ref/rpm/default.htm - FDA Compliance Policy Guides, Chapter 1-General and Chapter 2 - Biologics.http://www.fda.gov/ora/compliance_ref/cpg/default.htm
- Glossary of Computerized System and Software Development Terminology, August 1995.
- Guide to Inspection of Computerized Systems in Drug Processing, February 1983.
- PROGRAM CONTACTS:
- Division of Inspections and Surveillance, HFM-650
- Program Surveillance Branch, HFM-654
- Biological Product Deviations
- Division of Case Management, HFM-610
- CBER Sample Custodian, HFM-672
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
Sharon O'Callaghan, OCBQ/DIS/PSB, 301-827-6346
Beth Rogerson, OCBQ/DIS/PSB, 301-827-6220
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, Tissue Recall Orders, 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 Core Team contact:
Kara Lynch, HFC-100, 301-443-6230
Specialist Assistant to ORO
Kara.Lynch@fda.hhs.gov
Office of Enforcement
For questions pertaining to recalls:
Recall Operations Staff
Division of Compliance Management and Operations, HFC-210
Office of Enforcement
FAX 240-632-6859
Melvin Szymanski
240-632-6856
Melvin.Szymanski@fda.hhs.gov
Pete Cook
240-632-6857
Pete.Cook@fda.hhs.gov
For questions regarding compliance policy issues:
Division of Compliance Management and Operations, HFC-210
240-632-6850
FAX 240-632-6859
Fred Richman
Office of Enforcement, HFC-210
Fred.Richman1@fda.hhs.gov
Dr. Jacqueline Little, HFC-210
240-632-6863
OE/DCMO
Jacqueline.Little@fda.hhs.gov
PART VII - COORDINATION 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 evaluate the experience with this systems-based inspection program through inspection reports and other compliance data to determine its effectiveness and to assess and improve the quality of the CBER products inspection program. It also will review industry compliance, product developments within industry, and the safety and quality of CBER-regulated biological drug products will likewise be closely monitored.
ATTACHMENTS - Product Guidance
FRACTIONATORS
Plasma Fractionation
Blood plasma contains a mixture of thousands of different kinds of proteins, only a few of which are of therapeutic interest. To make plasma derivative products, plasma can be treated with a variety of substances to separate the desired proteins from others, in a process called fractionation. Cohn and co-workers at Harvard Medical School developed fractionation of plasma, from pools often derived from thousands of donors, during World War II. Today, most plasma derivative manufacturers use a modified Cohn method developed by Oncley (Cohn-Oncley fractionation process) or further variants of this method, which permit manufacture of additional products.
Fractionation by the Cohn-Oncley method relies on precipitation of plasma proteins by a combination of cold alcohol (usually ethanol)-water mixtures and adjustments of pH, ionic strength, temperature, and protein concentration. Alternatively, some manufacturers separate plasma derivatives by column chromatography using ion exchange, gel filtration, or affinity methods, without alcohol. In all cases, fractions of plasma are separated sequentially, with the product from one step, such as the precipitate and/or supernatant, becoming the starting material for the next step in the fractionation process. If each step is not done properly, subsequent fractions can be adversely affected. Thus, the integrity of each final product is dependent on all of the preceding steps in the process.
Plasma derivatives are similar to other biological products in that they are protein-based and subject to denaturization at high temperatures. These products are usually filled by using aseptic processing techniques, and cannot be terminally sterilized, although in some instances they can be heat- treated in the final container to effect viral inactivation.
Materials System
Source Material
The types of source material used and their suppliers are important. The material should be either licensed Source Plasma or unlicensed Recovered Plasma. Recovered Plasma is a product for which no published standards exist beyond labeling requirements included in 21 CFR 606.121. Licensed manufacturers must provide assurances that plasma for fractionation has been properly processed from the time of collection, and that it does not contain disease-causing agents or contaminants. The plasma for fractionation must be tested and found negative for Anti-HIV-1, Anti-HIV-2, Anti-HCV, HBsAg, and HIVag.
Recovered Plasma can be used if there is a valid short supply agreement in effect with each supplier (see 21 CFR 601.22). The only way in which unlicensed source material may be shipped for use in a licensed product is under short supply. The short supply agreement should include the manufacturer's acceptance criteria for the plasma, e.g., storage/shipping temperatures, viral testing, etc.
Storage of Bulk Fraction
Bulk concentrates should be held and stored in compliance with approved license applications and applicable regulations; see 21 CFR 640.81(d) for Albumin; 21 CFR 640.91(d) for PPF, and 21 CFR 640.102(c) for IG. Many manufacturers store bulk paste below -20 degrees C.
Production System
Pooling
At the minimum, it is recommended that pooling be conducted in an environmentally controlled, but not necessarily classified area (one with some level of particulate control). Manual pooling may take place either in jacketed tanks or in tanks in a temperature controlled area.
Fractionation
Control of the process is essential, since each step yields the starting material for the following steps in the process. Review of the firm's product specific flow diagram(s) may be useful in following the process.
Other areas to consider include; special centrifuges, collection of pastes (precipitates recovered by using centrifugation techniques or filter presses during the fractionation process), filter press operations, filter aid addition, and acetone drying process.
Column Purification
Column chromatography may be used for some plasma derivatives, e.g., coagulation proteins and some immune globulin products. Conditions for collection of active material should be well defined in batch records, and correctly controlled so as to exclude unrelated material.
Column cleaning, rinsing, testing for residuals, and regeneration procedures are very important. Columns not in use should be stored under conditions that inhibit microbial growth and prevent chemical or physical alteration of the medium.
Incubation
Following heat treatment, final containers of Albumin and PPF are incubated at 20-35 degrees C for at least 14 days; see 21 CFR 640.81(g) and 21 CFR 640.91(g).
VACCINES
There are many special public health considerations applicable to vaccines and their use. In most cases, vaccines are administered prophylactically, with the intent to stimulate the immune system, and reduce or prevent future occurrence of disease. Vaccines are, therefore, generally administered to healthy individuals, including small children and military personnel. Examples of standard childhood vaccines include; Diphtheria, Tetanus, and Acellular Pertussis; Inactivated Polio Vaccine; Haemophilus influenzae type b; Hepatitis B; and Measles, Mumps, and Rubella. Vaccines may be administered to individuals who have been exposed to a particular infectious agent, in an attempt to prevent the individual from developing the disease. Other vaccines may be administered to alter the course of a non-infectious disease, such as Bacillus Calmette Guerin for the treatment of bladder cancer. Vaccine related products, such as diagnostic skin test antigens, e.g. tuberculin, Coccidiodin, and Histoplasmin, identify persons having an immune response to a particular organism, which may be indicative of an infection.
Many vaccine manufacturers are sole suppliers of specific vaccines or related products.
Facilities and Equipment System
Cross-contamination is a significant concern in facilities that manufacture more than one product. There are specific regulatory requirements aimed at preventing cross-contamination with regard to spore-forming organisms and live vaccines. The regulations, found in 21 CFR 600.10 and 600.11, require that personnel, buildings, and equipment used for processing spore-forming organisms and live vaccines be isolated from other processes, so as to prevent contamination and cross-contamination.
Materials System
Active vaccine components are derived from many sources. A vaccine may be a live attenuated preparation of bacteria, viruses or parasites; inactivated (killed) whole organisms; irradiated cells; crude fractions or purified immunogens (including recombinant DNA derived products); synthetic antigens; or others. A vaccine product may include a combination of the sources described above. Vaccines may also contain adjuvants, which potentiate the immune response to the active component.
Production System
Cell Culture
Includes inoculation of the initial vessel with the starting materials and scale up.
Disruption and Harvest
Disruption (when appropriate) and harvesting of the product is performed using chemical, physical, or enzymatic means. All process parameters should be specified and documented in the batch production records.
Adventitious Agent Removal
For products derived from cells of human or animal origin, viral removal must be performed in accordance with the process described in the approved license application. In some manufacturing operations there may be a specific viral removal step. In other operations, viral removal may be accomplished by a step or series of steps in the manufacturing process, which are not specifically considered to be for viral removal, e.g., chromatography.
Purification
Purification of vaccine bulks may include one or more of the following methods:
a) Column or batch chromatography
b) Centrifugation
c) Filtration
d) Precipitation followed by filtration or centrifugation
Adsorption
Adsorption is the process of adding an aluminum adjuvant to a vaccine antigen in order to increase its immunogenicity. Aluminum adjuvants of various formulations are used in vaccine production. The vaccine manufacturer should specify the quality attributes of the adjuvant, including percent purity, particle size, and protein binding capacity. Quality attributes are generally specified on Certificates of Analysis (COA) provided by the adjuvant manufacturer. Batch records must specify the type of adjuvant used.
Aluminum adsorption may be performed on intermediates, bulks, or both. Two general procedures are used for aluminum adsorption: (1) addition of pre-formed aluminum adjuvant to vaccine antigens, and (2) on-site formulation of an aluminum adjuvant. For some vaccines, conditions for binding the aluminum adjuvant to the antigen may be known, and specifications will be established for this process. However, for many products, the scientific mechanism for binding the aluminum adjuvant to the antigen has not been determined, and therefore, no binding specifications will be established.
The extent of adsorption of an aluminum adjuvant to an antigen may be affected by production process parameters such as pH, phosphate concentration, and adequate mixing. These adsorption process parameters should be specified by the manufacture, in order to promote consistency in manufacturing.
Note: Products containing aluminum adjuvant are formulated aseptically because once they are alum adsorbed they cannot be sterile-filtered.
Inactivation
If the active ingredient of the vaccine is a killed or inactivated version of a live bacteria or virus, the methods for inactivation will have been established by the manufacturer and reviewed during product approval. Either heat or chemical treatment may be used for inactivation. All process parameters should be monitored and appropriate testing performed to demonstrate inactivation. Appropriate containment procedures should be established for the agent being inactivated.
If the active ingredient of the vaccine is a bacterial toxin, methods of toxin inactivation will also have been established by the manufacturer and reviewed during product approval. Treatment with formaldehyde is an example of toxin inactivation. All process parameters should be monitored, and appropriate testing performed to demonstrate inactivation of the toxin.
Conjugation
The chemical linkage of a polysaccharide immunogens to a carrier protein generally forms conjugate vaccines. Polysaccharide immunogens are extracted from bacterial cells. Carrier proteins are usually derived from bacterial cells that are different from those used to produce the polysaccharide. The polysaccharide immunogens and the carrier proteins are purified using a variety of methods including; centrifugation, buffer exchange, diafiltration, and chromatography. The purification process should be monitored through in process testing in order to assure the purity of the polysaccharide and carrier protein, and to assure removal of product and process related impurities. Specifications for in-process testing should be specified and results documented in the batch production records.
After purification of the polysaccharide and carrier protein, a chemical reaction(s) is (are) used to covalently link the two molecules together. The reaction should be monitored in order to determine completion of the conjugation reaction, amount of impurities, yield, and purity of the final conjugate product. Additional purification steps may be employed to remove excess reagents and reaction by-products. In addition, post-purification steps may be performed to produce a stabilized conjugate.
Endotoxin Levels
Some bacterial vaccines are manufactured from gram-negative organisms, which produce endotoxin. In these types of vaccines, the endotoxin is often the immunizing agent of interest, and the manufacturer will have defined specifications for endotoxin levels in the final product. The production and testing records should be routinely reviewed to assure that the final product meets the pre-defined endotoxin specifications.
Finished Products
For vaccines and related products, the biological drug substance may be diluted, adsorbed with adjuvant, mixed with stabilizers, mixed with preservative, and/or lyophilized to become the final finished product. In addition, more than one vaccine can be formulated together to produce a combination vaccine product. There are several different final container/ closure systems for vaccine products. Examples include capsules (blister packed), sachets, oral solutions, sealed glass ampules, single-dose syringes, single-dose and multi-dose vials (solutions or lyophilized), and multiple puncture devices pre-loaded with antigen.
RECOMBINANT PRODUCTS
While the specifics of each manufacturing operation may be different, the manufacture of recombinant biological drug products has a number of common elements. The process usually begins with a master cell bank (MCB), which is derived from a single cell or colony, and is stored to assure genetic stability. The MCB provides source material for the working cell bank (WCB), which is used to initiate the production batch.
One method of propagating sufficient cells to manufacture product is through fermentation. Fermentation is the process of multiplying the cells from the WCB into a quantity sufficient to extract the desired product. Cells from the WCB are inoculated into a medium to begin fermentation.
After a number of passages in small vessels (usually flasks), the inoculated medium is added to a fermentation vessel, usually a bioreactor. At the conclusion of the fermentation process, the cells are subjected to a variety of purification steps, which are designed to remove extraneous cellular material and/or media components, and inactivate or remove any adventitious agents.
Purification can include filtration, chromatography, extraction, and enzyme digestion. The resulting final bulk product may be filled in this form, further diluted and filled, or lyophilized before filling.
Components
Master Cell Bank (MCB) and Working Cell Bank (WCB)
- Storage Conditions
- Identification
- Handling of the WCB
- New MCB
The storage conditions for the MCB and WCB should be clearly defined, and a system in place to ensure that the storage conditions are maintained. If the storage requirements specify a temperature limitation, there should be documentation of routine temperature readings, and a working alarm system in place in case the temperature deviates from the established one.
There should be documentation that the WCB was characterized and met specifications before use. If any WCB that did not meet specifications was used, determine which lot(s) of product was manufactured from the WCB and the disposition of the product.
The firm should have records to show the origin and history (number of passages) of the MCB and WCB.
Review the records for inventory and handling of the WCB and ensure they are adequate to protect the integrity of the cells. Verify the firm has records to show which WCB is used to initiate a production batch.
The firm must have an approved license application or submit a supplement to its license before generating a new MCB from a WCB. The firm should also have records documenting that the new MCB was tested and properly characterized.
Endotoxins
Production should be performed in a controlled environment that prevents an increase in the product's microbial load beyond its design specifications. Procedures to prevent equipment or product contamination by any substance that could reasonably be expected to have an adverse effect on product quality should be in place and followed. Precautions should be taken to prevent contamination or cross-contamination in areas for the preparation of cell banks. Product manufacturing processes capable of promoting microbiological growth should be monitored for bioburden on a routine basis.
Fermentation/Bioreactors
The fermentation process includes inoculation of the initial vessel with the WCB and scale-up. Often the early passages are conducted in open vessels under laminar flow. The larger vessels are generally closed systems. If the system is closed, there should be no breaks in the system. All steps in the process should be recorded in the batch record.
Disruption and Harvest
Disruption (when appropriate) and harvesting of the product is performed using chemical, physical, or enzymatic means. All essential parameters should be documented.
Purification
Purification is generally performed using a combination of column chromatography, filtration and centrifugation. The method being used should be the same as the approved process and all steps should be documented in the batch record.
ALLERGENICS
Under the Public Health Service Act (PHS Act), CBER licenses allergenic products that are used for the diagnosis and treatment of individuals with sensitivity to various materials. Allergenic products are biological products that are administered to man for the diagnosis, prevention, or treatment of allergies. The products are manufactured from source materials that may include pollen, insects, mold, food and animals.
In addition to meeting the definition of a biological product, allergenic products also fall within the definition of a drug as found in Section 201(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Consequently, these products are regulated and inspected by authorities delegated under the PHS Act, the FD&C Act, and other authorities, including the applicable sections of the Biologics regulations (21 CFR Parts 600-680) and the Drug regulations (especially Parts 210 and 211, Current Good Manufacturing Practice).
Allergenics include injectable products, and allergen test patches. This program is not intended to address allergen test patches. Injectable products are provided to the practitioner as either ready to use (glycerinated, aqueous, or alum-bound) or as a lyophilized product plus diluent. If the product is supplied as a lyophilized product, the diluent is considered a component of the product. Injectable products are required to be sterile.
Standardized and Non-standardized
The FDA has determined that a number of allergenic products must be in a standardized form. Standardized allergens must be tested for safety, sterility, potency and identity, and stability. Standardized allergens are also subject to CBER lot release. Non-standardized allergens should be tested for safety and sterility. Exceptions to the testing required in 21 CFR 610.11 and 610.12 are found in 21 CFR 680.3(b) and (c).
Prescription Sets
The composition of prescription sets is generally considered to be the pharmacy practice (regulated by State authorities), and as such, is not subject to this program. However, investigators should confirm that the facility has a valid prescription on file for each set, and that the bulk or stock materials were manufactured in accordance with CGMPs. Prescription sets are manufactured from bulk or (licensed) stock concentrates in accordance with an individual physician's prescription.
Materials System
Source Material
The source material contains the active substance, which is responsible for the allergic response. Source materials and source material manufacturers are not required to register or list, and are not licensed. These materials are not finished biological drug products, so manufacturers are not held to the requirements in Part 211.
Source material suppliers are subject to the requirements in 21 CFR Parts 600-680. Specific criteria for source materials can be found in 21 CFR 680.1(b) and (c). Because source materials are components of a biological drug, they must be manufactured in accordance with the general principles of CGMPs.
Most finished product manufacturers obtain their source materials from source material suppliers. If the finished product manufacturer manufactures its own source materials, the source material manufacturing operations should be inspected, if it is within the same facility or a facility in close proximity to the finished manufacturing site.
Per 21 CFR 680.1(c), allergenic product manufacturers must list with CBER the name and address of each source material supplier. The list must be updated annually. The source material suppliers should be the same as those reported to CBER.
Animal Source Materials
Animals of the equine genus are treated to maintain immunity to tetanus and reports of any diseases in 680.1(b)(3)(iv) should be reported to CBER as required.
1. Seed Banks
Master Viral Seed (MVS) and Working Viral Seed(s) (WVS)
By definition, a WVS consists of material having the same composition and origin, with a specific lot number and date of manufacture, and, in many cases, is one passage removed from the MVS. The MVS, and at least one WVS, should be qualified for use during the licensing process. The firm should have a complete history for the MVS and the WVS, including the passage history and testing profiles for each. The storage and handling of the viral seeds and the use of WVS in vaccine manufacture are extremely important. Batch records should clearly indicate the WVS used.
New Viral Seed
A new MVS for a licensed product requires a CBER approved supplement prior to release of any vaccine derived from the new MVS. A new WVS must be reported to CBER, either as a prior approval supplement, CBE-30, or, with appropriate documentation, in the annual report. If the manufacturer has changed either the MVS or WVS since licensing or the previous inspection, the change should be reported to CBER in the appropriate manner. If a new viral seed was produced, there should be records describing the production of the new viral seed to assure that the viral seed was produced without deviations from the appropriate regulations and license requirements.
Storage
Maintenance of the MVS and the WVS under tight security is necessary, inasmuch as these items are an integral part of the production process. The viral seeds should be stored separately, in multiple locations, at the appropriate temperature, with adequate controls to prevent unauthorized access and loss of material due to equipment failure. The storage conditions, including temperature, should be clearly defined, validated, and documented. A working alarm system for each storage location is frequently seen.
Inventory
The firm must maintain an accurate inventory of all viral seed stocks, and each sample of viral seed must be clearly marked to indicate its contents. The inventory records should correlate to the amount of material on hand. The firm should maintain adequate control of WVS samples destined for use in production in order to assure protection of the samples and personnel safety.
Suitability of the WVS
The manufacturer should be able to provide data (e.g., titer, sterility) supporting the continued suitability of the current WVS for use in manufacture.
Bacterial Primary seeds and Secondary (Working) seeds Storage conditions
Maintenance of both the primary and the working seeds under tight security is necessary, as they are an integral part of the production process. Bacterial primary seeds should be stored separately, in multiple locations, at an appropriate temperature, with adequate controls to prevent unauthorized access and loss of material due to equipment failure. The storage conditions, including temperature, for the primary and secondary seeds should be clearly defined and documented. A working alarm system for each storage location is frequently seen.
Identification
The history and characteristics of each bacterial strain used in the manufacture of a product should be maintained. Characterization may include origin of the isolate, speciation, serotyping, biochemical testing, virulence, genetic characterization, and in-vivo animal or human testing. The primary and secondary seeds should meet specifications prior to use in production and appropriate records of characterization should be maintained. The manufacturer should have records to demonstrate which secondary seed lot is used to initiate a production batch.
Seed Integrity and Passage Limitation
In order to maintain genetic stability of the bacterial strain, the number of passages permitted for primary and secondary seeds are limited. The number of passages should be specified in an appropriate SOP based on the number of passages approved in the license application. Lot number and date of preparation should identify primary and secondary seed lots. Periodic tests should be performed in order to verify the integrity of the strain characteristics and freedom from contamination with extraneous organisms. Appropriate records should be maintained detailing the number of passages of each primary and secondary seed, and all tests performed to demonstrate strain integrity and freedom from contamination.
New Primary and Secondary Seeds
A change in a primary seed requires submission and approval of a supplement (prior approval supplement or PAS) prior to use of the primary seed in production. Establishment of new secondary seeds from a previously approved primary seed may be submitted to CBER as a CBE-30 supplement or in an annual report, provided that the change is made according to an SOP in the approved license application, unless otherwise specified.
2. Cell Banks
Master Cell Bank (MCB) and Working Cell Bank (WCB)
Cell bank systems are used for storage of some cell lines that are used as hosts for viral propagation. Both the MCB and WCB are qualified for manufacture during the licensing process. In most instances, a MCB is more extensively characterized than the WCB, although a manufacturer can be licensed for a product where the WCB is more extensively characterized than the MCB. In the latter case, the following comments for a MCB would be applied to the manufacturer's WCB.
Storage Conditions
The storage conditions for the MCB and WCB should be clearly defined. The MCB should be stored in more than one location, in the event that the MCB stored in one location is destroyed. Personnel access to both the MCB and WCB should be clearly specified and tightly controlled. Maintenance of the storage conditions should be assured. Storage requirements specifying temperature limitations, should document conditions and a working alarm system should be in place for temperature deviations from the established limits.
Identification
The cell bank should be well-characterized, and meet specifications prior to use in production. Any new WCB should be reported to CBER in the appropriate manner. If an approved procedure is in place, production of a new WCB according to the approved procedure may represent a minor change to be included in the annual report of minor manufacturing changes.
A cell bank that did not meet specifications should not be used. In the event this did occur there should be a record of an investigation, which includes a determination of how it happened, and the disposition of the lot(s) manufactured from the cell bank. The number of passages or doublings of a cell bank is controlled in order to assure genetic stability and, for attenuated vaccines, freedom from virulence. The number of permissible passages or doublings is product specific and will be specified in the firm's approved license application. The firm should have records identifying the passages and/or doublings of the MCB and WCB according to the procedures specified in the approved license application.
Handling of the Cell Bank
Storage, inventory, and handling of the MCB and the WCB should be adequate to protect the integrity of the cells with documentation to support. The firm should maintain records identifying the cell bank used to initiate a production batch and, if diploid cells are used for production, that the cells were utilized at the appropriate passage levels, as specified in the license.
Viral Safety Evaluation of Cell Banks
Because cell lines are derived from human or animal hosts, viral safety testing is often required in order to assure that the cell lines are free from contaminating viral agents. Viral contaminants may originate from the host cell itself (endogenous), or may be introduced into the cell line during production (non-endogenous).
Tests performed on the MCB or WCB to demonstrate the absence of adventitious agents are specified in the license application or approved supplements. For some products, each batch of production cells is also tested for possible viral contaminants that may have arisen during production.
New MCB and WCB
Establishment of a new MCB requires a license application or prior approval supplement. Establishment of a new WCB from a previously approved MCB may be reported in an annual report, provided that the WCB was generated in accordance with an SOP on file in an approved license application. A new WCB should be from an approved MCB. The testing of the new WCB should be performed in accordance with the SOP in the approved application or as submitted in a prior approval supplement.
3. Cell/Seed Expansion
Cell Culture
The process includes inoculation of the initial vessel with the starting materials and scale-up. Often the early passages are conducted in open vessels under laminar flow. The larger vessels are generally closed systems. There should be no breaks in connections between processing vessels in a closed system.
Fermentation/Bioreactors
The fermentation process includes inoculation of the initial vessel with the WCB and scale-up. Often the early passages are conducted in open vessels under laminar flow. The larger vessels are generally closed systems. There should be no breaks in connections between processing vessels in a closed system.
4. Viral Clearance
Products derived from cells or source material of human or animal origin, viral inactivation/removal should be performed in accordance with the process in the approved license application. In some manufacturing operations, there will be a specific viral inactivation/removal step; in other operations, viral inactivation/removal will be accomplished by a step or steps in the manufacturing process that are not specifically considered to be viral inactivation/removal steps. In some instances more than one viral clearance step is used for a given product.
There should be complete segregation of pre-and post-viral inactivation/removal steps (with the exception of products such as Albumin, which are virally inactivated in final containers). Separate areas with a dedicated air handling unit or single pass air should be used for those steps that occur after viral clearance procedures.
Heat treatment is one method of clearing infectious agents from biologicals. Heat treatment is sometimes referred to as pasteurization, and heating equipment such as large water baths, may be referred to as pasteurizers. Technically, however, pasteurization is heating at 63 degrees C for 30 minutes, which is not sufficient to render plasma derivatives virally inactive.
The parameters specified in the batch record should be achieved such that the validated process for viral inactivation/removal is accomplished. Changes made to the process, which do not require submission of a supplement to CBER, should be validated.
5. Inactivation
If the active ingredient is a killed or inactivated version of a live bacteria or virus, the methods for inactivation will have been established and reviewed during product approval. Either heat or chemical treatment may be used for inactivation. The manufacturer should have validated the process and followed the validated procedures during production. All parameters should be monitored and the appropriate testing is performed with acceptable results. The containment procedures should be adequate for the agent being inactivated. If the active ingredient is a bacterial toxin, methods of toxin inactivation will also have been established and reviewed during product approval. Treatment with formaldehyde is an example of toxin inactivation. As stated above the manufacturer should follow validated procedures for toxin inactivation, perform appropriate testing to demonstrate inactivation of the toxin, and obtain test results that are within the specifications approved in the license.
6 - 7. Disruption and Harvest
Disruption (when appropriate) and harvesting of the product is accomplished using chemical, physical, or enzymatic means. The firm should only be using their approved method(s) and all essential parameters should be documented.
8. Purification
Purification is generally performed using a combination of column chromatography, filtration and centrifugation. The method being used should be the same as the approved process and all steps should be documented in the batch record.
8a) Column or Batch Chromatography
Column or batch chromatography may be used for the purification of plasma derivatives, bacterial, viral and recombinant products. Conditions for collection of active material should be well defined in batch records and correctly controlled so as to exclude unwanted material. Transfers should be made in an environmentally controlled system.
Column cleaning, rinsing, testing for process residuals, leaching from column media, and regeneration procedures are very important. These procedures must be validated and followed. There must be a defined and validated number of times a column may be re-used, and this limit must be followed.
Validation of production scale columns must be performed. This validation may be performed concurrently, and may be in progress. Columns not in use must be stored under conditions that inhibit microbial growth and prevent chemical or physical alteration of the medium. A system must be in place to monitor column performance, so that if the column begins to degrade or perform outside the validated parameters, it can be immediately replaced or regenerated, as specified by appropriate SOPs, and supported by process validation. Column support equipment such as UV monitors, pumps, chart recorders, PLCs, etc., should have appropriate installation qualification (IQ), and operational qualification (OQ). These should also be included in routine calibration schedules. Firms should document calibration, maintenance, replacement, and upgrades; these operations should be performed in accordance with SOPs.
8b) Centrifugation
Low-speed, high-speed, ultra-centrifugation or continuous flow centrifugation methods are commonly used in harvest and purification schemes. Centrifuge run time and speed (rpm), specific equipment number (if more than one option), and rotor used should be documented in the batch production record. Centrifuges should have appropriate equipment validation, IQ, OQ and performance qualification (PQ), and should be re-certified/calibrated on a regular basis to assure that the specified time and rpm produces the desired relative centrifugal force (rcf), to achieve adequate separation. Routine maintenance should include examining the rotors for wear. Rotors should be dedicated to the product or have a validated cleaning procedure. The centrifuge rotors as well as the inside of the centrifuge should have a validated cleaning process, as this technique commonly produces aerosols. The centrifugation step should have been included in the overall process validation, so that the stated time and speed reliably produce the desired separation. Any changes in the centrifugation equipment (new rotors, and especially a new centrifuge) should be in accordance with SOPs and documented. For example, 3200 rpm at 20 minutes in one brand of a centrifuge may not achieve the same rcf as the same time and speed in a similar-looking instrument from another manufacturer.
8c) Filtration
There are various types of filtration methods, such as diafiltration, ultrafiltration and microfiltration that may be used in the purification of vaccine products. Some of the filters used may be single-use and some may be multi-use. The filters are usually placed within a filter housing apparatus. The criteria used for the evaluation of the column purification should also be applied to the filter housings and the multi-use filters.
8d) Precipitation followed by Filtration or Centrifugation
Conditions for precipitation (time, temperature, concentration, etc.) should be based on process validation and be defined in the batch production record. Previous comments regarding filtration and centrifugation apply, as appropriate.
9. Formulation, Filling, and Packaging
For some biological drug products, the drug substance may be diluted, adsorbed with adjuvant, mixed with stabilizers, mixed with preservative, and/or lyophilized to become the final biological drug product. In addition, more than one component can be formulated together to produce a combination vaccine product.
10. Filtration
The sterilizing filters should be validated for product compatibility and microbial retention and that they are adequate for their intended use. The filters should be evaluated prior to use to determine if they meet specifications. Integrity testing should be performed on filters post-fill and results should be in keeping with the manufacturer's validated specifications. Some bulk products are held after sterile filtration prior to filling. The holding period and storage conditions should be validated.
11. Filling
If the duration of filling is lengthy, time limits should be established and validated to ensure that the duration of the fill does not affect the potency of the product and its susceptibility to microbial contamination. An SOP should be in place for interruptions in the fill, should it occur. Some products are held after sterile filtration prior to filling. The holding period and storage conditions should be validated. Filling lines should be inspected to ensure that carryover does not occur from previous fills.
12. Lyophilization
Loading of the lyophilizer should be done either under Class 100 (ISO 5) conditions, or as otherwise approved by CBER. The lyophilization process must be performed in accordance with validated parameters, including the placement of products in the lyophilizer.
If the vials are overlaid with gas (usually nitrogen) the firm's procedures for integrity testing of sterilizing filters, sterilization, and replacement, should be documented and followed.
13. Containers/Closures
There are several different final container and closure systems for biological drug products. Examples include capsules (blister packed), sachets, oral solutions, sealed glass ampules, single-dose syringes, single-dose and multi-dose vials (solutions or lyophilized), and multiple puncture devices pre-loaded with antigen. The firm should have 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.
The firm should have procedures and controls used to verify and assure suitability of containers and closures, for accepting/rejecting final product containers and closures from the vendor, a validated container/closure system(s) and for the reconciliation of final containers.
The depyrogenation and sterilization procedures for product containers, closures, and components should be appropriately validated, and followed. Equipment used for these processes (stopper processors, tunnel sterilizers, ovens, autoclaves) should be properly maintained and re-qualified periodically.
14. Labeling/Packaging
Applicable labeling requirements are found in 21 CFR 201, as well as various sections of Parts 610 and 660. Specific wording for labeling is reviewed and approved by CBER. Products should be labeled as approved by CBER.
Process controls during labeling and packaging, such as inspection, label security, and label accountability, should be written and followed. Visual inspection should be performed in appropriate areas, and operators should be trained and certified in visual inspection procedures.
15. Aseptic/Controlled Process:
Biological products are manufactured in a controlled environment. The entire process does not have to be performed under aseptic conditions, but the firm should have established the point in the process where aseptic controls begin. Products should be maintained in a controlled environment throughout the process and have specified in-process bioburden action and alert limits for which the firm can provide a meaningful rationale.
a. Aseptic processing from early manufacturing steps:
Some products undergo aseptic processing at some or all manufacturing steps preceding the final product closing step. With some products, there is a point in the process after which a product can no longer be rendered sterile by filtration. In such cases, the product should be handled aseptically at all steps subsequent to filter sterilization. In other instances, the final biological drug product cannot be filter sterilized, and, therefore, each component in the formulation should be rendered sterile and mixed aseptically. For example: products containing aluminum adjuvant are formulated aseptically because once they are alum adsorbed, they cannot be sterile-filtered.
When a product is processed aseptically from the early stages, the product and all components or other additions are rendered sterile prior to entering the manufacturing process. It is critical that all transfers, transports, and storage stages be carefully controlled at each step of the process to maintain sterility of the product.
Procedures (e.g., aseptic connection) that expose a product or product contact surfaces must be performed under unidirectional airflow in a Class 100 (ISO 5) environment. The environment of the room surrounding the Class 100 (ISO 5) environment must be Class 10,000 (ISO 7) or better. Microbiological and airborne particle monitoring should be performed during operations.
Microbial surface monitoring should be performed at the end of operations, but prior to cleaning. Personnel monitoring should be performed in association with operations.
Process simulation studies should be designed to incorporate all conditions, product manipulations, and interventions that could impact on the sterility of the product during manufacturing. The process simulation, from the early process steps, should demonstrate that process controls are adequate to protect the product during manufacturing.
These studies should incorporate all product manipulations, additions, and procedures involving exposure of product contact surfaces to the environment. The studies should include worst-case conditions such as maximum duration of open operations and maximum number of participating operators. Process simulations do not need to mimic total manufacturing time if the manipulations that occur during manufacturing are adequately represented.
It is important that process simulations incorporate storage of product or transport to other manufacturing areas. For instance, there should be assurance of bulk vessel integrity for specified holding times. The transport of bulk tanks or other containers should be simulated as part of the media fill. Process simulation studies for the formulation stage should be performed at least twice per year.
For lyophilization operations, unsealed containers should be exposed to pressurization and partial evacuation of the chamber in a manner that simulates the process. Vials should not be frozen, as this may inhibit the growth of microorganisms.
b. Aseptic processing of cell-based therapy products (or of products intended for use as cell based therapies)
Cell-based therapy products represent a subset of the products for which aseptic manipulations are used throughout the process. Where possible, closed systems are used during manufacturing. Cell-based therapy products often have short processing times at each manufacturing stage, even for the final product. Often, these products are administered to patients before final product sterility testing results are available. In situations where results of final sterility testing are not available before the product is administered, additional controls and testing could be instituted. For example, additional sterility tests can be performed at intermediate stages of manufacture, especially after the last manipulation of the product prior to administration. Other tests that may indicate microbial contamination, such as microscopic examination, gram stains, and endotoxin testing should be performed prior to product release.
c. Manufacturing and aseptic processing
The manufacturer must meet their established microbial specifications for in process testing for the lots made. Observation of the aseptic processes should be made, when possible, to evaluate aseptic technique. All connections and transfers to manufacturing should be made in an aseptic manner.
An SOP should be in place for interruption of the fill, should it occur. Some bulk products are held after sterile filtration prior to filling. The holding period and storage conditions should have been validated. Procedures should be in place for limiting access to controlled and classified areas.
Filters should be evaluated prior to use to assure they meet specifications. Integrity testing should be performed on filters post-fill and results should