FDA Reporting Categories for Manufacturing Site Transfers and Additions: PAS vs CBE-30 for NDAs and BLAs

FDA reporting categories for manufacturing site transfers and additions: NDAs and BLAs (PAS vs CBE-30)

FDA does not put every site transfer or site addition in one reporting category. For both NDAs and BLAs, the category depends on the change's potential to adversely affect product quality as it relates to safety or effectiveness. Substantial potential calls for a prior approval supplement (PAS). Moderate potential generally calls for a changes-being-effected-in-30-days supplement (CBE-30), with an immediate CBE available in certain circumstances. Minimal potential is documented in the annual report (AR) ²⁴. For site changes, three factors largely decide where a move lands:

1. The operation being moved. Examples include sterile versus nonsterile manufacture, dose-controlling primary packaging, drug substance versus intermediate, and testing.
2. The destination's CGMP inspection status for that specific type of operation.
3. Whether the move comes with other changes. If it does, the whole package is assessed as a multiple related change.

Key takeaways

• NDA default: Moving drug product, in-process material, or drug substance manufacture to a different site is generally a CBE-30 ²¹⁰. It becomes a PAS when the new site has never been inspected for the operation, has no satisfactory CGMP inspection for it, or is restarting an operation it stopped more than two years ago ³²¹³²².
• Product-driven PAS triggers (NDA): A PAS is also required for the following moves:
  • modified-release products or products whose primary packaging controls the delivered dose ³²³
  • aseptic processing moves into new, refurbished, or "dissimilar" aseptic areas ³²⁴
  • terminally sterilized product moved to a newly constructed facility at a different site ³²⁵
• BLA default (certain biological products): Adding or replacing a facility, or a building within an approved location, that makes drug substance, drug product, or intermediates is a PAS ²⁸⁹²⁹⁰. A new suite or room within an approved building can be a CBE-30 only if sterility assurance and contamination or cross-contamination are not affected ²⁹⁰²⁹¹.
• Lower-risk operations: Secondary packaging and labeling site changes are generally AR for both NDAs and BLAs, provided CGMP status is acceptable ^13829329529. Primary packaging and testing laboratory moves generally sit at CBE-30 or CBE for NDAs ¹³⁷²⁸³.
• Downgrade mechanisms: An approved comparability protocol or ICH Q12 PACMP can justify a lower category. FDA warns, however, that a reduction may not be justified for site changes that need facility evaluation or a preapproval inspection ¹⁶¹²⁸¹.

The NDA framework: Changes to an Approved NDA or ANDA

Under FDA's Changes to an Approved NDA or ANDA guidance, a move to a site not listed in the approved application must be reported. This applies whether the site is owned by the applicant or by a contractor ¹³⁵. If the site move also involves changes to the process or equipment, FDA expects the applicant to evaluate it as a multiple related change rather than as a site move alone ²⁴¹.

Reporting categories for NDA site changes

FDA's guidance generally does not require moves of production operations within the same site to be reported, subject to its stated exceptions ²⁵⁰. FDA also notes that the AR category is based on the change's potential for adverse effect. Favorable supporting results alone do not turn a change that belongs in a supplement into an AR change ²⁵¹.

CGMP inspection status as the deciding factor

FDA recommends a PAS for an otherwise moderate or minor site move if the new site lacks a satisfactory CGMP inspection for the type of operation being moved ¹⁴³. FDA's examples make clear that the inspection status must match the specific operation:

• Satisfactory status for capsule and powder manufacture did not support moving immediate-release tablet manufacture to the site.
• A packager's satisfactory status for capsules did not support moving tablet packaging there ^143207208.

Satisfactory status for a profile class code generally covers the products and operations within that code's category. It does not necessarily extend to a different dosage form or operation ³²⁷. For purposes of this guidance, FDA places no time limit on a satisfactory inspection unless the type of operation was discontinued ³²⁸.

Sterile products

For aseptically processed product, the line between CBE-30 and PAS depends on whether the destination aseptic area already manufactures similar approved products. FDA gives an example of a PAS case: transferring a lyophilized product to an existing aseptic area that has no approved lyophilized products, or whose approved products use different container types or sizes ²¹⁵. Other moves to aseptic facilities or areas are CBE-30 ²³².

For terminally sterilized products, the first transfer to a newly constructed facility at a different site requires a PAS. After that approval, later moves of similar product types and processes into the same facility may be submitted as CBE-30 ³²⁵³²⁶. The NDA guidance passages reviewed set out these categories and the CGMP qualification. They do not prescribe a site-transfer package of media fills, sterility assurance studies, or validation batch counts ¹²⁵.

Packaging, labeling, and testing laboratories

• Primary packaging: generally CBE-30 unless it falls under a listed major change ¹³⁷.
• Secondary packaging: generally AR ¹³⁶.
• Labeling sites: generally AR. A labeling site is one that labels primary or secondary packaging components. Putting identifying information on the dosage form itself counts as manufacturing or processing ^138113139.
• Container-closure preparation: Sterilizing or washing container-closure components is drug product manufacturing. Moving bottle fabrication or packaging resin manufacture need not be reported if nothing else changes ²¹⁴. A move to a different site for certain packaging-component sterilization can be reported in the AR if the process is not materially different and the facility has a satisfactory CGMP inspection for the operation ¹⁵⁸.

For analytical testing laboratories, PAC-ATLS: Postapproval Changes — Analytical Testing Laboratory Sites allows a CBE supplement when all four of the following conditions are met ²⁸³²⁸⁴:

1. Approved methods (or methods implemented under 21 CFR 314.70(d)) are used.
2. Postapproval commitments relating to those methods have been fulfilled.
3. The new facility can perform the testing.
4. The new facility has had a satisfactory CGMP inspection within the past two years.

The supplement should include:

• a written statement explaining why each condition is met
• the new site's name and address
• a full description of the testing the site will perform
• clear identification as a PAC-ATLS filing ¹⁴²

Test-transfer data generally need not be included. For biological tests, however, comparative data from an approved site and the new facility should be included, except for pyrogen and bacterial endotoxin tests ²⁸⁵. Changes outside PAC-ATLS default to a PAS ¹⁴². PAC-ATLS predates the 2004 Changes to an Approved NDA or ANDA guidance, which lists a qualifying move to a different testing site as a CBE-30.

Drug substance and intermediate sites

For data on intermediate-site transfers where the synthetic pathway stays the same, BACPAC I (a joint CDER/CVM guidance, also numbered CVM GFI #126) recommends that the submission:

• identify the new facility
• describe the transferred steps and any differences in equipment or operating conditions
• state that the synthetic pathway is identical
• evaluate impurities and physical properties using three consecutive batches from the new site compared against historical data
• provide a validation summary for new analytical procedures ¹⁵⁰

If impurity profiles or relevant physical properties are not equivalent, an applicant that wishes to proceed should submit a PAS and consider case-specific studies, such as impurity qualification or bioequivalence ²⁵³.

FDA's draft Postapproval Changes to Drug Substances guidance (not for implementation) addresses a new API source involving multiple changes. It proposes:

• a risk assessment supporting the chosen reporting category
• three pilot- or commercial-scale API batches
• specified API and drug product stability data
• at least one pilot- or commercial-scale drug product batch ¹⁴⁸¹⁷⁰

Supporting data for NDA drug product site changes: the SUPAC framework

The SUPAC guidances define site change levels and the data FDA expects for each. They cover a change in location only, not simultaneous changes to formulation, equipment, or process. New locations should have a satisfactory current CGMP inspection ¹⁸³¹⁸⁴. The SUPAC guidances predate the CBE-0/CBE-30 split; the 2004 Changes to an Approved NDA or ANDA guidance controls the reporting category, and SUPAC is mainly a guide to the supporting documentation.

At Level 3, therefore, the dosage form determines the filing. A different-campus transfer of a modified-release product requires a PAS. A different-campus transfer of an immediate-release tablet or a nonsterile semisolid is filed as a changes-being-effected supplement. Across SUPAC levels, the core NDA data package is consistent ^104185108186:

• new site identification
• updated or executed batch records
• release testing against application or compendial requirements
• a comparative in vitro performance test (dissolution or in vitro release) for higher levels
• accelerated stability data in the supplement, with long-term stability commitments

The BLA framework: certain biological products

For the biological products covered by Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products, the appendix examples separate new manufacturing locations from changes within an approved location.

Adding a drug product at a multiple-product contract manufacturing site already listed in an approved BLA is an AR example, but only if stated identity-testing, changeover, and no-added-risk conditions are met. This is not a general AR route for moving manufacture to a new contract manufacturer ²⁹⁷.

FDA's companion guidance, CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports, lists the following as AR examples, subject to its exclusions for certain QC testing:

• site changes for certain testing
• site changes for labeling or secondary packaging

Facilities used for these site changes should meet CGMP requirements ²⁹³⁰³¹.

Product-specific guidances add further detail:

• Glass vials and stoppers: A change in the sterilization site for vials or stoppers is a CBE-30, supported by the new site's name and address and sterilization validation data. A change in the testing site is AR ²⁷³².
• Blood and blood components: Under the blood and blood components change guidance, facility and contractor changes require a PAS unless that guidance specifies another category ²⁵.
• Collection facilities under a protocol: A new collection facility implemented under an approved comparability protocol is an example of a CBE-30 ²⁶²⁸⁰.

Supporting data FDA expects for biological product site transfers

For postapproval changes, FDA expects the submission to include, as appropriate:

• data showing comparability of pre- and post-change intermediates, drug substance, or drug product
• identification of the affected sites
• an explanation of the change and its quality assessment
• relevant validation protocols and data

The applicant should ensure appropriate CGMP status, and FDA may inspect as part of its review ¹¹. Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products similarly calls for study data, validation protocols and data, and affected-site information in major-change supplements ⁵⁸.

FDA's guidance on pilot manufacturing facilities addresses transferring a biological product to a new facility. It calls for:

• a description of the manufacturing changes
• data comparing product made at the old and new facilities
• process validation and stability data for product made at the new facility
• a demonstration of product consistency
• confirmation that the facility is ready for inspection ^5354555657

For a proposed manufacturing site change to a BLA deemed licensed under the BPCI Act, the supplement must assess the change's effects, support the safety, purity, and potency of material made after the change, and include pre- and post-change comparability information ³³.

On stability, FDA's draft revision of Q1 Stability Testing of Drug Substances and Drug Products (not for implementation) recommends a comparability assessment for an additional site. This would compare accelerated and/or stressed stability results from commercial-scale batches at the new site against primary batches from the original site. The draft allows a justified, risk-based reduction in the production-scale stability data submitted initially, with a commitment to continue studies at each site up to a total of three production-scale batches ³⁷. The biological product guidance passages reviewed do not set a universal number of conformance lots or a transfer-specific environmental monitoring package ⁴²¹¹.

Lowering the reporting category: comparability protocols and PACMPs

Under Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA, an FDA-approved comparability protocol can typically move a change that would ordinarily need a PAS down to CBE-30 or CBE-0, and an ordinary CBE change down to AR ¹⁶¹. The protocol should prospectively specify the tests, studies, and acceptance criteria that will show no adverse effect on quality, preferably with side-by-side comparison of pre- and post-change attributes ²⁷⁶. For certain biological products, the comparability protocol is itself submitted as a PAS, and the applicant should request the reduced category and obtain FDA's approval of it as part of the protocol ²⁷⁷.

Site changes have limits that a protocol cannot get around:

• FDA may need to consider inspection history, experience with the dosage form, and the quality system at the time of implementation, and may require a preapproval inspection.
• A facility that is not in acceptable CGMP compliance for the operation at that time requires a PAS.
• A move that needs an in vivo bioequivalence study is generally not suitable for a comparability protocol ²⁸¹.

Under ICH Q12, a PACMP is an approved agreement that specifies the change, how it will be verified, and its acceptance criteria. It also proposes a lower reporting category and/or a shorter review period ²⁷⁸.

The Q12 Annex example for adding an alternative drug substance site describes ^311312279:

• comparative analysis of three consecutive batches from the new site against the approved specification
• completed technology transfer and process qualification
• stability studies started on commercial-scale batches of both the drug substance and the drug product made with it

For a process transfer to a recipient site, the Annex describes the following, with the number of validation batches set on a risk and process basis ^313197314:

• side-by-side analytical characterization
• comparable process performance attributes
• degradation studies
• a validation plan at step 1 and summary validation data at step 2

The Annex proposes implementation at a lower submission category than existing regulations would otherwise require, or a submission type eligible for accelerated review, depending on regional requirements. It does not name a specific category ³¹⁵.

Practical implications for site change strategy

• Start with the operation and the destination's inspection history. For NDAs, a drug product move to a site with satisfactory CGMP status for the same type of operation is the typical CBE-30 case ²¹⁰¹⁴³. Any of the following moves the change to a PAS:
  • no inspection history for that operation ³²¹
  • modified-release or dose-controlling packaging ³²³
  • a "dissimilar" aseptic area ³²⁴
• For BLAs, assume a new facility or building is a PAS. CBE-30 is generally limited to suites or rooms within approved buildings that do not affect sterility assurance or contamination control, and to primary packaging sites with acceptable CGMP status ^289290293.
• Package data to the risk. For NDAs, the SUPAC framework sets dissolution or in vitro release, batch record, and stability expectations by dosage form ^104108188. For biologics, FDA expects pre- and post-change comparability, validation data, and stability data from the new site ¹¹⁵³.
• Plan downgrades early. A comparability protocol or PACMP can support CBE-30 implementation for later site additions. FDA's acceptance of the reduced category still depends on facility and inspection considerations ^161277281.

Questions this overview leaves open include product-specific precedents in Drugs@FDA approval packages, how FDA has treated multi-site BLA strategies for specific modalities, and how established conditions under ICH Q12 have been applied to site changes in individual applications.