How to manage the risk of foreign visible particles in ATMPs
by Elena Meurer and Noemi Lupo
Advanced Therapeutic Medicinal Products (ATMPs) are a class of innovative medicinal products comprising gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (sCTMP), tissue-engineered products (TEP) as well as combined ATMPs (ATMPs associated with medical devices). ATMPs represents a novel treatment approach for severe diseases with unmet medical need and have been rapidly evolving in recent years, being seen as the medicine of the future by many. As novel product class, ATMPs require application of novel manufacturing strategies, which represents a great learning process for both ATMP manufacturers and their material suppliers. One change of the manufacturing paradigm is represented by an intensive use of disposables instead of multi-use sterilised equipment for aseptic manufacturing. Single use materials provide certain advantages in terms of ensuring sterility for relatively small batches, although their use is often driven by the absence of other manufacturing solutions. Currently, the utilisation of single use equipment is seen as established for cell-based products. For manufacturing of large quantities of adherent cells with several passages, the numbers of disposables used can easily extend to hundreds of units (flasks, syringes, connectors, pipets, bags and vials – there is a huge diversity, and each particular product may require specific equipment).
With ATMPs being a young product class, the criteria for their quality are also still evolving. One of the quality criteria which is currently getting more and more into focus is related to the presence of visible particles in the final product. Not to the last extent, this attention is initiated by the extensive manufacturing use of plastic disposables potentially shedding such particles. Both Ph.Eur. and USP distinguish between visible and subvisible particles. Visible particles are defined as particles of size which can be seen by the unaided eye, typically in the range of 100 µm and larger. This distinction is of great importance as a large size of particles – beside their nature and shape – is generally considered to be one of risk factors for parenteral administration, although it is not unambiguously confirmed by clinical findings. Indeed, according to Ph. Eur. and USP parenteral preparations such as infusions should be free of visible particles [1, 2].
For ATMPs, the freedom from particles is often an impossible goal as such products by themselves consist of particles, i.e. viral particles and cells provided in form of suspension. Moreover, common purification techniques used to remove non-product related particles from parenteral drugs, such as terminal sterilization or filtration using small pore filters (<0.5 μm) are not applicable to ATMPs often having a size above 10 µm (i.e some viral particles and cells). Furthermore, tests for visible particle determination described in Ph. Eur. 2.9.20 and USP<790> are based on the inspection of the sample against white background followed by a black background in the presence of a qualified light source. These methods are primarily developed for batches of sterile parenteral products (not necessarily ATMPs) consisting of hundreds or thousands of units. As visible particles can be assumed to be heterogeneous and non-uniformly distributed across a given parenteral product batch, a sufficiently large number of samples has to be analyzed. A 100% inspection of a batch and rejection of non-conforming units is expected where statistical principles cannot be applied, e.g. for small size batches. As ATMPs batches often consist of one or just a few units, rejection of units containing visible particles would compromise the whole batch, further emphasizing the importance of particle prevention.
The challenge in the control of visible particles and the establishment of acceptance criteria on the statistical basis for products available in limited number of units such as ATMPs is also discussed in the recently introduced informative non-mandatory Ph.Eur. chapter 5.17.2. Recommendations on testing of particulate contamination: visible particles. In many respects this new chapter follows the considerations expressed in USP monograph <1790> published a few years ago. Although both Ph.Eur. 5.17.2. and USP<1790> state that the claim ‘zero particles’ remains the goal, it is not considered to be a realistic quality control acceptance criterion since the probabilistic nature and random occurrence of visible particles often leads to the discovery of single particles in single units. Furthermore, “practically free” should reflect the capabilities of the manufacturing and testing process. Therefore, an appropriate approach must be defined for each product.
Another important aspect for the assessment of the risk represented by visible particles in parenteral preparations is the determination of particle sources. Based on their origin, particles are classified as extrinsic, intrinsic, and inherent according to USP<1790>, where extrinsic particles constitute the highest risk. According to the Ph. Eur. 5.17.2., particles may be extrinsic (deriving from the environment, equipment, primary packaging or personnel) or intrinsic (related to the formulation, including active substances and excipients, process residuals or contaminants, or resulting from interactions between the formulation and primary packaging). These definitions are different in USP<1790>, where extrinsic (or exogenous) particles are defined as those foreign to the manufacturing process. These particles may carry an increased risk of microbiological or extractable contamination, because less is known about their path prior to deposition in the product container or their interaction with the product. Intrinsic particles may come from processing equipment or primary packaging materials that were either added during processing or not removed during container preparation. These particles might still be associated with the risk of a foreign body, but generally come from sterile or sanitized materials and more is known about their interactions when in contact with the product. Inherent particles are those to be or intended to be associated with specific product formulations.
Ultimately, the safety aspects related to particulate matter need to be assessed for each individual ATMP and require a case-to-case approach addressing the totality of introduced measures and establishing appropriate acceptance criteria, as summarized in Figure 1.
Given the variety of ATMPs, manufacturing processes and clinical indication, individual solutions are required for each particular case, which should be worked out in a risk-based approach. We at Biopharma Excellence have a proven track record of establishing successful ATMP quality strategies and will gladly support you in designing the path forward when dealing with the matter of visible particles in ATMPs products. If interested, please do not hesitate to contact us.
 Ph. Eur. General chapter Parenteral preparations (0520)
 USP General chapter Injections
Ph. Eur. 2.9.20 (Particulate contamination, visible particles)
USP <790> (Visible Particulates in Injections)
Ph. Eur. 5.17.2. (Recommendations on testing of particulate contamination: visible particles)
USP<1790> (Visible Inspection of Injections)