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Manufacturing Biological Intermediates and Biological Drug Substances Using Spore-Forming Microorganisms: Guidance for Industry

FinalCenter for Biologics Evaluation and Research09/01/2007
Process ValidationValidationQualificationCurrent Good Manufacturing PracticeEnvironmental monitoringQuality control unit review

Description

The former regulations at 21 CFR 600.11(e)(3) (§ 600.11(e)(3)) required that all work with spore-bearing microorganisms (spore-formers) be conducted in an entirely separate building, or in a completely walled-off portion of a multiproduct building. This isolated building had to be dedicated exclusively for the manufacturing or storage of spore-formers.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

4
Biological Intermediates

Manufacturing biological intermediates using spore-forming microorganisms; manufacture, processing, packing or holding of drugs, including biological intermediates

Biological Drug Substances

Manufacturing biological drug substances using spore-forming microorganisms; manufacture, processing, packing or holding of drugs, including biological drug substances

Biological drug product

Finished dosage form containing an active biological drug ingredient.

Biological drug substance

Extrapolation rules for well characterised biologicals; Less amenable to modelling by humidity modified Arrhenius equation

Stakeholders

1
Manufacturer

Entity responsible for submitting NDINs

Regulatory Context

Regulatory Activities

1
Decommissioning

Process of closing a dedicated spore-former manufacturing area.

Document Types

1
Standard operating procedures

SOPs describing the manufacturing process for CSP

Attributes

3
Specificity

Ability to detect intended mechanism of action without interference; Performance characteristic to be validated

Crossover point

The processing point where viable organisms are not part of the process

Detection Limit

Analytical procedure validation characteristic

Technical Details

Substances

5
Spore-Forming Microorganisms

Organisms capable of spore production used in manufacturing; guidance does not apply to spore-forming microorganisms used for supplemental sterilization procedure control tests; The primary biological agent requiring containment and decontamination.

Spore-forming microorganism

Organisms that are capable of spore production, including both spore and vegetative forms

Recombinant Proteins

Alternatives for second-generation vaccines

Chlorine dioxide

Substance used for sanitizing.

Hydrogen peroxide

CAS# 7722-84-1; Chemical inducing oxidative stress; PDE of 68,000 µg/day based on endogenous production; Hydrogen peroxide (CAS# 7722-84-1) potential for human exposure and mutagenicity; Compound-specific acceptable intake calculation for hydrogen peroxide

Testing Methods

2
Environmental Monitoring

Used to determine frequency of filter changes; Guidelines for Listeria testing of environmental samples

Matrix approach

Method recommended for developing the number of samples for testing.

Processes

6
Aseptic Processing

implied manufacturing process under QS regulation

Decontamination of spore-forming microorganisms

A process that eliminates or inactivates viable bioburden and any associated toxic material

Sterilization

Required for contaminated equipment and media before disposal

Decontamination

Basic specimen manipulation step

Sterilize-In-Place

utilizing a decontamination chamber system such as an autoclave, sterilize-in-place (SIP) cycle

Campaign changeovers

The process of cleaning and decontaminating an area between different products.

Clinical Concepts

1
Anthrax

Example of a disease condition where route of exposure affects progression

Identified Hazards

Hazards

1
Cross-contamination

Risk associated with construction, traffic flow, and shared equipment.; Risk from raw food to RTE food or from insanitary objects; Personnel handling RTE foods touch contaminated surfaces

Related CFR Sections (2)

See Also (8)

Manufacturing Biological Intermediates and Biological Drug Substances Using Spore-Forming Microorganisms: Guidance for Industry | Guideline Explorer | BioRegHub