Current GMP milestones
Throughout the stage of development of a mAb product, production
quantities differ, starting with micrograms to grams for research and
toxicology studies, to tens to a few hundred grams for early-stage
clinical studies, to up to hundreds of kilograms for late-stage
clinicals trials and licensed production (Carson, 2005). Manufacturing
facilities must therefore suit the needs and requirements of production
throughout clinical development. As the resulting DP from downstream
processing is ready to be administered into patients, precautions and
regulations must be taken and followed to assure product quality,
safety, traceability and reproducibility. Regulatory health authorities
such as World Health Organization (WHO), FDA and EMA have described and
constantly audit the so-called current Good Manufacturing
Practices (cGMP). GMP outlines measures to ensure that processes
necessary for production and testing are clearly defined, validated,
reviewed and documented. By these definitions, products are ensured to
be produced and controlled according to quality standards appropriate
for their intended use and as required by product specification.
Manufacturers and their facilities located in the European Economic Area
(EEA) must hold authorization issued by a national competent authority
and must comply with European Union (EU) GMP to obtain authorization.
The national authorities are then responsible to inspect manufacturing
sites and ensure they are effectively following the EU GMP guidelines
(European Medicines Agency, 2016). The GMP guidelines are based on the
following principles (WHO, 1998):
- Manufacturing facilities must maintain a clean and hygienic
manufacturing area.
- Controlled environmental conditions to prevent cross-contamination of
drug products from adulterants that may render the product unsafe for
human consumption.
- Manufacturing processes are clearly defined and controlled. All
critical processes are validated to ensure consistency and compliance
with specifications.
- Manufacturing processes are controlled, and any changes to the process
are evaluated. Fluctuations that affect the quality of the drug are
validated as necessary.
- Cross-contamination with unlabelled major allergens is prevented.
- Records are kept (either manually or electronically) during
manufacturing that demonstrate that all steps required by the defined
procedures and instructions were in fact taken and that the quantity
and quality of the drug was as expected. Deviations are investigated
and documented accordingly.
- Records of manufacture, including distribution enable the complete
history of a batch to be traced back. These records are retained in a
comprehensible and accessible form.
- The distribution of drugs minimizes any risk to their quality.
- A system is available for recalling any batch from sale or supply.
- Complaints about marketed products are examined, the causes of quality
defects are investigated, and appropriate measures are taken with
respect to the defective products and to prevent recurrence.
With the strict implementation and control of GMP, the drug product is
guaranteed to be safe and traceable. Deviations and variations can be
easily tracked, and action can be taken accordingly to avoid putting the
patient at risk or losing drug efficacy throughout the process.