Inspection of Biological Drug Products

In January 2010, the FDA published the revised Compliance Program Guidance Manual Chapter 45 Biological Drug Products – Inspection of Biological Drug Products.
This compliance program combines and replaces the compliance programs for licensed allergenics (7345.001), licensed vaccines (7345.002), plasma derivatives (7342.006) and therapeutic drugs (7341.001)and should ensure that CBER-regulated biological drug products for human use are safe, pure, potent, effective, and appropriately labeled. Facility inspections should be made in a way that make sure, that the manufacturer meet the standards described in applicable provisions of the regulations like 21 CFR Parts 600, 601, 610, 640, 660, 680, and 1271,  like the CGMP regulations in Part 200, 201, 210 and 211 or other applicable standards.
The Compliance program provides guidance to investigators who have to perform inspections at manufacturers of biological products based on the two years inspection rhythm as well as case-related.

This chapter includes information regarding noncompliance with applicable regulations, provides information necessary to evaluate overall operations, including quality assurance and quality control programs of the inspected facilities, and ensures that appropriate enforcement actions are initiated against those manufacturers found to be in significant noncompliance with applicable laws and regulations.

In the revised version several minor changes happened e.g.:

- Part E: Inspectional Guidance - Point 6 - Biologic Product Deviations (BPDs)

Previous text:
Under 21 CFR 600.14, a manufacturer must report any event associated with the manufacturing, including testing, processing, packing, labeling, or storage, or with the holding or distribution of a licensed biological product, which may affect the safety, purity, or potency of a distributed licensed product.
BPDs are required to be reported to the CBER/OCBQ/DIS as soon as possible, but no later than 45 calendar days from the date of discovery of information reasonably suggesting a reportable event has occurred. Under 21 CFR 600.14, the manufacturer who holds the biologics license and who had control over the product when the deviation or unexpected event occurred must report a BPD.
If a manufacturer contracts out any manufacturing step, that manufacturing step is performed under the manufacturer’s control under the regulation. Thus, under 21 CFR 600.14(a), the manufacturer must establish a procedure for receiving information from that contract manufacturing facility on all deviations, complaints, and adverse events that may affect the product. A contract manufacturer (i.e., performs, under contract, a step in manufacturing for another facility) must conduct manufacturing in accordance with all applicable regulations. Determine if any reportable event, which may have occurred, have been reported to CBER. Contact OCBQ/DIS if confirmation of reportability to CBER is required.

New Text:
Under 21 CFR 600.14, a manufacturer must report any event associated with the manufacturing, including testing, processing, packing, labeling, or storage, or with the holding or distribution of a licensed biological product, which may affect the safety, purity, or potency of a distributed licensed product.
BPDs are required to be reported to the CBER/OCBQ/DIS as soon as possible, but no later than 45 calendar days from the date of discovery of information reasonably suggesting a reportable event has occurred. Under 21 CFR 600.14, the manufacturer who holds the biologics license and who had control over the product when the deviation or unexpected event occurred must report a BPD.
If a manufacturer contracts out any manufacturing step, that manufacturing step is performed under the manufacturer’s control under the regulation. Thus, under 21 CFR 600.14(a), the manufacturer must establish a procedure for receiving information from that contract
manufacturing facility on all deviations, complaints, and adverse events that may affect the product. A contract manufacturer (i.e., performs, under contract, a step in manufacturing for another facility) must conduct manufacturing in accordance with all applicable regulations.
CBER provides ORA with direct access to BPD information through CEARS (CBER Error and Accident Reporting System). CEARS only captures the reportable events. Instructions for accessing the system are found on the CEARS intranet web page.

To facilitate industry reporting of BPD, CBER developed a standardized reporting format (FDA Form 3486) with both hard copy and electronic reporting. CBER encourages electronic reporting. Prior to conducting an inspection, investigators should review the manufacturer's BPD
submissions in CEARS. An assessment of the deviation codes may assist you in determining the optional system to inspect. Otherwise, select a representative sample of reports to verify the adequacy of the firm's corrective action.

• Evaluate both reportable deviations and non-reportable incidents or problem reports and verify the adequacy of any corrective action implemented by the manufacturer.
• Determine if the manufacturer filed all reportable biological product deviations.

It is FDA policy to only cite on a Form FDA-483 a deficiency associated with a previously-reported BPD if the establishment's investigation or corrective action was inadequate.

- Part F : Reporting:
Previously text:
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.

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

To see the complete new document, please click here.

Author:
Axel H Schroeder
On behalf of the European Compliance Academy (ECA)

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