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FDA letter reveals particle size critical to GMP compliance
Hørsholm, Denmark: – Particle Analytical, the Danish-based CRO that specializes in analysis of particle properties, warns that a recent letter from the US Food & Drug Administration (FDA) should serve as a wake up call for the pharmaceutical and fine chemicals industries.
Following two out-of-specification (OOS) investigations of Indian-based manufacturer Cadila Healthcare Ltd in August-September and December last year, the FDA’s Chief Scientific and Compliance Officer, Dr. Rebecca Parrilla, warns the company that particle size data is a critical parameter in OOS investigations.
FDA inspectors found that Cadila’s investigations into warfarin tablet failures were ‘inadequate’, with consequent recurrence of product quality failures indicating that the company’s corrective and preventive actions (CAPA) were ineffective.
Particle size influence on manufacturing quality
“The recurrence of these failures is apparently due to inadequate identification of root causes and lack of action to resolve this manufacturing problem,” commented Dr. Parrilla.
“Your response to this letter should discuss any further work to remediate the process (such as improving process design) and quantify the reliability of equipment used in the manufacture of warfarin that can affect content uniformity, assay, thickness, or other relevant critical quality attributes,” she continued.
A key passage of her warning letter states: “In evaluating equipment reliability, you should use methods such as rolled throughput yield and discrete process capability estimates. Also discuss your evaluation of other influential factors on manufacturing consistency. Include the role of particle size and the potential significance of (b)(4) particles on (b)(4). Finally, provide your justification for continued production and explain how you have ensured that your marketed product is safe.”
Warning passed on
The FDA warning was spotted by Particle Analytical CEO, Søren Lund Kristensen, who has posted it on his LinkedIn page, commenting that the passage is directly linked to Q6 of the Good Manufacturing Practice (GMP) guidelines, where it is stated that particle size is a critical factor affecting production, stability, content uniformity, bioavailability and appearance.
“The point is that particle size affects so many critical aspects of your product so you must remember to investigate this when there is a quality issue or OOS/OOT regarding a product,” Lund Kristensen points out.
“It is important to investigate the particle size if all other factors do not indicate a clear root cause for failing results,” he says.
Particle Analytical advises manufacturers to check six key aspects of particle size control:
- Was particle size measured at all?
- Has something changed in the manufacturing, drying or handling of the API?
- Is the shape of the particles unchanged?
- Has particle characterization data been collected on all solid materials involved in process, apart from the active pharmaceutical ingredient (API)?
- Do particle size measurements vary from specification or show any obvious trends or variations when compared with historical data?
- Were all results generated using the same validated method?
Need for method evaluation
The Danish laboratory also advises manufacturers to have a specialist evaluate their methods of analysis.
“Sometimes OOS can reveal that an old method is no longer working sufficiently well or that something was overlooked during product development,” says Kristensen.
He advises manufacturers that formal method investigation is important to identify any possible variations in how analyses were performed or to identify obscure issue, such as sedimentation before sampling.
“Could it be that some hitherto unknown factor, such as surface area or content of amorphous material, has affected the product? If all other indications do not show a clear root cause, perhaps have somebody investigate if there is an unknown (not routinely measured) physical aspect influencing the quality parameters,” he suggests.
About Particle Analytical
Particle Analytical ApS is a contract laboratory (CRO) that specializes in analysis of physical parameters of particles, powders or emulsions, using a range of advanced techniques.
Founded in year 2000, the laboratory has become one of Denmark’s most rapidly expanding companies, twice winning the national ‘Growth Gazelle’ award.
It is one of the few laboratories in Europe to offer a complete range of services dedicated to analysis of powders, including particle size, and all physical chemical properties. These services are primarily focused on the pharmaceutical industry, where particle and powder analysis are essential in controlling compound properties during development, both with regard to production process and behavior in vivo.
Unique analysis services include determination of refraction index, fast compatibility screenings of excipients and determination of the crystalline proportions of samples.
Particle Analytical’s leading-edge capabilities include laser diffraction, XRD, thermal analysis, dynamic light scattering, microscopy, BET, dynamic vapor sorption, density measurement and air permeability. The laboratory is fully certificated as cGMP compliant by the Danish authorities and is also registered with the US Food & Drug Administration (FDA).
Particle Analytical services can either be used in routine analysis, separately to solve specific problems, or in parallel to larger drug development programs. These services include particle size determination, examination of physical properties, polymorph screening, method development and validation.