GMP Regulations
The FDA’s requirements for pharmaceutical and biologics manufacturing are outlined in 21 CFR Parts211 and 600 [3, 4], commonly referred to as Good Manufacturing Practice (GMP) regulations. Under 21 CFR 210.2, investigational products used in clinical trials are subject to phase appropriate GMP requirements, with specific exemptions varying by the stage of clinical development [5]. For example, an investigational product in Phase I may be exempt from specific GMP requirements that are required for an investigational product at pivotal clinical trial stages. Sponsors are encouraged to consult FDA and ICH guidance documents to understand which exemptions are permitted at each phase of clinical development [6, 7]. When applying for a biologics license, GMP regulations apply for the manufacture of the commercial product.
Preclinical Manufacturing
Advancing a laboratory made construct into an investigational product meeting GMP standards involves adapting small scale experimental methods into reproducible manufacturing processes suitable for human trials. Preclinical manufacturing requires iterative formulation and process development followed by scale up and qualification. One or more development batches are manufactured prior to production under GMP. These batches will typically differ in facilities, equipment, materials, reagents, and methods used compared with the GMP batch (see Development Batches). Commonly referred to as toxicology, pilot or engineering batches, these early manufacturing cycles produce drug product material that can be used for preclinical (nonhuman) IND studies. The information described in this section is intended to provide a general overview of common process development and other types of non-GMP batches to allow Sponsors to maximize the use of material from these production runs for use in translational research. In this context, note the following important considerations:
The FDA does not define or recognize the terms research, toxicology, pilot or engineering batches and there are no industry definitions or standards that characterize these non-GMP batches. CDMOs may use different names and apply different conditions, depending on their facilities, equipment and procedures. Sponsors and CDMOs typically manufacture one early batch that is specifically for use in toxicology studies.
The FDA does not recognize descriptions such as “GMP-like” or “GMP-equivalent”; research, toxicology, pilot or engineering batches are, by definition, not GMP.
Sponsors planning to use material from non-GMP batches as test articles for IND-enabling in vivo or in vitro studies should discuss these plans with the FDA in a Pre-IND meeting. A description of the batch and how it compares with a batch made under GMP conditions should be detailed in the meeting package. Should the Agency agree, a comparative analysis based on analytical data of the non-GMP versus GMP batch will be required in the IND.
Development Batches
The following is a summary of common types of non-GMP development batches. Characteristics will vary by CDMO; consultation with the contracted CDMO is strongly advised.
Research Batch
Experimental products made in an academic laboratory or commercial manufacturer development laboratory.
Use of research quality materials and reagents using bench top equipment.
Minimal quality testing; usually performed in a research and development laboratory with minimal or no specifications.
Batch size is very small
Typically used for discovery, early development, and proof-of-concept (POC) studies. Not recommended for GLP animal toxicology studies.
Not for use in human clinical trials.
Toxicology Batch
Manufactured in a controlled space but unlikely to be in a fully GMP suite.
Includes tests for quality; acceptance criteria for non-compendial methods are typically recorded as “for-information-only” or “report results”. SOPs are followed but may not include formal QA review and approval of processes and batch records.
May use a combination of GMP quality and research quality materials and reagents.
Batch size is small (e.g. 50L for gene therapies)
May be used for:
Analytical method development.
GLP animal toxicology studies*.
Preliminary stability studies*.
Other in vitro or in vivo experiments required for the IND*.
Not for use in human clinical trials.
Pilot or Engineering Batch
Pilot or engineering batches are intermediate manufacturing batches serving as a transition from development to full-scale manufacturing to generate data on yield, scalability, and product quality. Pilot or engineering batches are not offered by all CDMOs. An engineering batch is typically closer to GMP with respect to scale, equipment, facilities and batch records compared with a pilot batch.
The following general characteristics apply to either of these types of intermediate batches:
Intended as a trial run for GMP utilizing fully developed methods and specifications to qualify process steps before full-scale GMP manufacturing.
Uses GMP quality materials and reagents.
May be produced in small-scale fermenters (e.g. 200L for gene therapies) but still insufficient for clinical trial volumes (e.g. 1000L for gene therapies)
Used to optimize manufacturing protocols.
The batch record, Certificate of Analysis, Certificate of Testing or other comparable records from either a pilot or engineering batch may be included in the IND as representative of a GMP batch. Acceptance by the FDA will depend on the Sponsor’s ability to demonstrate comparability to GMP using analytical data and a comparison of processing, methods, materials and specifications.
May be used for:
GLP animal toxicology studies*.
Formal stability program*.
Other in vitro or in vivo experiments required for the IND*.
Assay qualifications.
Not for use in human clinical trials.
*Based on agreement with the FDA.