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New guidelines and best practices may lead to improved quality and reduced recalls due to visual defects.
Improving understanding and practice of visual inspection of parenteral drugs is a high priority for pharmaceutical companies and industry associations. The Parenteral Drug Association (PDA) and the United States Pharmacopeial Convention (USP) have been working to educate and provide guidance to the industry in the hope of establishing consistent, practical guidelines and best practices that will lead to improved quality and reduced recalls due to visual defects. Pharmaceutical Technology spoke with John Shabushnig, PhD, principal consultant at Insight Pharma Consulting, group leader for PDA’s Visual Inspection of Parenterals Interest Group, and a member of the USP Visual Inspection Expert Panel, about guidance from USP and industry best practices.
USP guidancePharmTech: United States Pharmacopeia(USP) General Chapter <790> ‘Visible Particulates in Injections’ became official in August 2014 (1). Can you comment on the sampling plan and acceptance criteria that the chapter provides to help define that a product is ‘essentially free’ from visible particulates?
Shabushnig: I think the ANSI/ASQ Z1.4 (2) or ISO 2859 (3) sampling plans are widely used and generally accepted by industry and regulators. These are the same general plans used to sample components before use as well as in support of batch release. The actual sampling plan chosen from these standards to achieve the level of protection specified is based on the size of the batch or lot produced. There are varying levels of understanding of how these plans should be applied and the level of protection the various sampling plans provide. The USP Expert Panel believes an acceptable quality level of 0.65% is an appropriate general value for application to particles in injections based on the current understanding of the risk of potential harm to patients. I think it is still early to know how widely accepted this value is or will be. Based on the regulatory emphasis and large number of recalls associated with particles in recent years, many companies have implemented tighter internal limits to define ‘essentially free’ [from visible particulates]. I also see some confusion about the application of the special sampling plans referenced in the standards and recommended for use when supplemental testing is required. Such testing is performed when the container or the formulation makes thorough inspection difficult. This testing is in addition to the non-destructive inspection of all units in the batch (100% inspection). Since these tests are destructive, such as reconstituting a powder or removing the contents from a dark amber vial or translucent plastic container, the number of units tested must be smaller than what is used for non-destructive testing.
The new chapter was discussed extensively at the PDA Visual Inspection Interest Group meetings this year as well as at the PDA Visual Inspection Forum. USP offered a live webinar on this chapter along with another on the subvisible particle chapters <787> (4) and <788> (5) in December 2014. I expect education activities and further discussion to continue in 2015 through both of these organizations.
PharmTech: Is there consensus on ‘essentially free’ when applied to particulates? What effect have you seen in industry practice as a result of this guidance?
Shabushnig: I believe there is a developing consensus on what is meant by ‘essentially free’ as now defined in USP <790>. Certainly there may be special circumstances where a tighter limit may be required for certain high-risk patient groups or routes of administration. These are discussed in an industry position paper drafted by a team of inspection experts and medical officers brought together by PDA earlier this year. This paper, an ‘Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products,’ is scheduled for publication in the PDA Journal of Science and Technology early in 2015. It supports the general concepts in USP <790> and provides guidance on assessing patient risk for the inadvertent administration of small numbers of particles.
PharmTech: What are the key points of the draft information chapter on visual inspection?
Shabushnig: USP <1790> ‘Visual Inspection of Injections’ was recently published (6) in draft form with the opportunity for all stakeholders to comment. USP <790> benefited from this commenting and revision process. General chapters by design are typically short and specific to the test method and acceptance criteria. Information chapters permit further discussion on the points to consider and the concepts behind the methods described in the general chapters. USP <1790> contains discussion of the key elements of an effective inspection process. It addresses visual inspection in general, including container and closure defects, as well as particles, which are the central focus of USP <790>. It contains discussion on patient risk and risk factors. It further develops the concepts of a lifecycle approach to inspection with the goal of defect prevention through continuous process improvement. It emphasizes gaining process knowledge through inspection, and not just sorting and removing nonconforming units. It provides more information on defect types and classifications as well as discussing the three common modes of visual inspection: human manual visual inspection, semi-automated inspection, and fully automated visual inspection. There is also discussion on the qualification of human inspectors and the validation of automated systems.
Best practicesPharmTech: What are the most important actions companies need to take to be sure that their inspection systems are following good practices?
Shabushnig: I believe it is important to understand the specific inspection process in use for the products that a company manufactures. What can be detected and removed during 100% inspection will vary with product formulation and with different primary packaging types. This also is important to determine if supplemental destructive testing, as previously described in USP <1> ‘Injections’ and now in USP <790>, is needed. Such testing may involve dissolution of a powder or freeze-dried cake or removal of the contents of a darkly colored or non-transparent container to assess if previously unseen particles are present. It is important to have a good list of defects so it is clear what the inspectors need to find. This is based on the nature of the product as well as an understanding of observed defects and potential production process and materials failure modes. This list, often supported by photographs and physical samples, provides a good foundation for inspector training and qualification as well as equipment validation. Finally, I also believe it is important to track and trend inspection results to support continuous process improvement.
PharmTech: What are some of the key results from the PDA VI benchmarking survey?
Shabushnig: Inspection practices are generally in alignment with the current conditions specified in USP <790>. Typical rejection rates are between 1-2%. The most common reason for rejection continues to be particles, with fibers being the type of particle most often observed.
PharmTech: Inspector training seems to be key. What best practices do you recommend for inspector training and qualification?
Shabushnig: As stated earlier, start with a good list of expected defects supported by photographs and physical examples. Provide sufficient time to practice the inspection technique to gain proficiency. Then document inspection ability with a good test set. This set should be different than the training set and not have too high a defect rate so as to provide an experience comparable to routine inspection. When assessing performance, be sure to set a time limit on completing the test that aligns with normal production inspection rates and also have a limit on the number of good units that can be falsely rejected, so that test results are not biased.
Inspecting biopharmaceuticalsPharmTech: What are some unique inspection challenges for biopharmaceutical products?
Shabushnig: Biopharmaceutical products are often sensitive to shear. Care must be taken when swirling the product so as not to damage the therapeutic proteins. USP <787> ‘Subvisible Particulate Matter in Therapeutic Protein Injections’ (4) was recently published to address some of these issues for subvisible particle measurement. Concerns of damaging the drug molecule are especially true when considering a high-speed spin available in most semi-automated and automated systems when inspecting for particles in the visible size range. The other issue that arises is that of ‘inherent’ particles. These are particles formed from protein agglomerates. Through clinical testing and the regulatory approval process, such particles may be shown to be safe and insignificant to efficacy. The difficulty is then ignoring these insignificant particles but still remaining sensitive to extrinsic and intrinsic particles.
AcknowledgementShabushnig: I would like to acknowledge my fellow members of the USP Visual Inspection Expert Panel, who wrote Chapters <790> and <1790>: D. Scott Aldrich, Ultramikro; John Ayres, Eli Lilly; Roy Cherris, Bridge Associates International; Desmond Hunt, USP; Steve Langille, US FDA; Russell Madsen, The Williamsburg Group; and Deborah Shnek, Amgen.
1. USP General Chapter <790> “Visible Particulates in Injections”(US Pharmacopeial Convention, Rockville, MD, 2014).
2. American Society for Quality, ANSI/ASQ Z1.4 Sampling Procedures and Tables for Inspection by Attributes (Milwaukee, 2013).
3. ISO, ISO 2859-1 Sampling procedures for inspection by attributes--Part 1: Sampling schemes indexed by acceptance quality limit (AQL) for lot-by-lot inspection (Geneva, 1999).
4. USP General Chapter <787> “Subvisible Particulate Matter in Therapeutic Protein Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).
5. USP General Chapter <788> “Particulate Matter in Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).
6. USP Draft Chapter <1790>, “Visual Inspection of Injections,” Pharmacopeial Forum 41 (1) Jan-Feb. 2015.
Article DetailsPharmaceutical Technology
Vol. 39, Issue 2
Citation: When referring to this article, please cite as J. Markarian, “Improving Visual Inspection Practices,” Pharmaceutical Technology 39 (2) 2015.