Description
This guidance describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). Building on existing International Council for Harmonization (ICH) Quality guidances, this guidance provides clarification on CM concepts and describes scientific approaches and regulatory considerations specific to CM of drug substances and drug products.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
7Scope of the analytical procedures
RTRT and CTD sections apply to drug substances
Scope of the analytical procedures
Proteins that reduce proinflammatory cytokines and affect CYP enzyme expression
Annex I and II focus on small molecule continuous manufacturing; Scope includes CM for chemical entities.; Drug products discussed in Annex II
Guidance topic regarding classification categories
CM system design can enable process intensification for therapeutic protein drug substance manufacturing.
Stakeholders
1Bodies that accept clinical trial data and grant marketing authorizations.
Regulatory Context
Regulatory Activities
3Used for assessment of batch quality in CM.
Studies required when converting from batch to CM
FDA review of process models and manufacturing data
Document Types
4Format for submitting development information; Module 3 of the CTD for detailed descriptions of analytical procedures; ICH guideline M4Q(R1) for the registration of pharmaceuticals.
Drug substance and drug product information could be provided in the respective CTD sections
approved design space described in the dossier
Section III.A of the guidance.
Attributes
10Characterizes the time available for material transport and transformation.; RTD is evaluated for the purposes of system integration and material traceability.; RTD used to determine diversion strategy and sampling frequency; A measure of the range of residence times experienced by material passing through a process.; Characterization used to define material traceability and diversion strategy; relevant risk to evaluate in surge tanks; Process steps for drug substance and drug product manufactur
assessment of process capability may be warranted
Impurity profile, polymorphism, particle size
Institution of a hold time enables temporary storage of drug substance
Drug substance stability data to define a retest period
specifications for the purity, strength, and composition of dietary supplements
quality attribute monitored during drug substance manufacturing
quality attribute that can be monitored via online release tests
Measure of the period between thawing MCB and harvesting.
Critical quality attribute for the primary excipient
Technical Details
Substances
6Input material where lot-to-lot variability impacts therapeutic protein processes.
Drug product specification should include elemental impurities
Drug product specification should include residual solvents used in drug substance synthesis
A material produced during steps of the synthesis that undergoes further molecular change.
Finished dosage form undergoing stability testing
Postapproval changes to drug substances; the active pharmaceutical ingredient being modified; Evaluation of physical properties for drug substance; Active ingredient intended to furnish pharmacological activity; The molecule or ion responsible for the physiological or pharmacological action.; The active pharmaceutical ingredient subject to postapproval changes
Testing Methods
10Process monitoring for therapeutic proteins
predictions based on an RTD model can be a useful tool to understand the qualitative and quantitative impact
quantitative high performance liquid chromatography (HPLC) analysis to relate the quantity of those compounds
Allowable variations identified through DOE or other suitable studies
new technology for real-time decision making
used for real-time monitoring in the control strategy; measurement of the drug substance concentration at a suitable location (e.g., NIR measurements at the tablet press feed frame)
Studies used to evaluate feeder mass flow rates
PAT tool used to monitor blend uniformity; monitored closely using NIR method
PAT is used to monitor conversion and measure impurities.
Application of multivariate statistical techniques to analyze complex process data.
Processes
10Considerations for batch selection in continuous processes; Stability data package requirements apply to CM processes; Manufacturing process impacting batch selection for stability; Alternative to batch processes for drug production; Manufacturing process referenced in ICH Q13
described in CTD section 3.2.S because it is related to concentration of the drug substance
Consisting of blending, granulation, drying, milling, compression and coating
Used to obtain the drug substance as a highly concentrated crystal slurry
End-user sterilization validation
used for buffer exchange and concentration
step in the continuous downstream process
unit operation for purifying target proteins
Process consisting of continuous feeding, blending, and tablet compression
Process used to ensure consistent quality of drug substance; Used to obtain the drug substance as a highly concentrated crystal slurry
Identified Hazards
Hazards
7Control strategy for therapeutic proteins in CM
managing transient disturbances that may occur during CM
Impurity carryover from the drug substance into the drug product should be provided
Safety concern regarding viral contamination
Potential risk for cleaning strategy and monitoring
Risk assessment performed for in-process materials
risk in multidose drug products
Standards & References
External Standards
1European Pharmacopoeia referenced for statistical process control.
Specifications
8limits for solid state form and particle size; Tightening acceptance criteria; Numerical limits or ranges for tests
disturbances meet criteria but occur with high frequency
would not cause the drug concentration in the blend to exceed the 90 to 110 percent label claim
considered a critical quality attribute for the drug substance
considered a critical quality attribute for the drug substance
Attributes typically associated with the drug substance quality are generally included in the drug product specification
Document where Class 2 and Class 3 impurities are listed
Risks to CQAs associated with facility or process changes
ICH References (10)
The CTD — Quality
applicable to drug product made by an integrated process
Referenced regarding specifications and solid state forms.
Recommendations for cell bank stability
Analysis of the Expression Construct in Cells used for Production of r-DNA Derived Protein products
Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin
Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management; referenced for established conditions and life cycle management tools; in line with recommendations described in ICH Q12; Guideline for technical and regulatory considerations for pharmaceutical product lifecycle management; Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.
Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process
Quality of Biotechnological Products: Stability Testing
Stability Testing of New Drug Substances and Products
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- DSCSA Implementation: Product Tracing Requirements — Compliance Policy
- E6(R3) Good Clinical Practice: Annex 2
- Consumer Antiseptic Rub Final Rule Questions and Answers Guidance for Industry: Guidance for Industry
- Best Practices for Communication Between IND Sponsors and FDA During Drug Development
- Botanical Drug Development: Guidance for Industry
- Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry
- Reformulating Drug Products That Contain Carbomers Manufactured With Benzene
- ANDA Submissions -- Refuse-to-Receive Standards Rev.2