Introduction
Pharmaceutical product container closure systems (CCS) should be designed to ensure that a drug product (1) is protected from factors that may impact product quality over its shelf life, including light, evaporation, exposure to gases, absorption of water, or microbial contamination; (2) is compatible with the selected CCS and that there is a lack of product—CCS interactions that might lead to a loss of potency due to absorption, degradation, or precipitation; and (3) that CCS manufacturing materials are safe for use with the dosage form and the route of administration. In addition, if the CCS has a performance feature, the assembled CCS should be demonstrated to function properly.1
In the case of sterile products, a failure of CCS integrity may impact patient safety due to potential for product contamination. In this paper, we will provide FDA’s current expectations on information to be submitted to new applications for sterile products, with emphasis on container closure integrity (CCI). We will include case studies to illustrate the impact of inadequate CCS or manufacturing conditions on product safety and we will provide examples on how a robust container closure integrity test (CCIT) method may prevent product failure. In addition, we will provide examples of recalled products different from the case studies but with similar root-cause failures.
Regulatory Framework
The control of drug product (DP) container and closures is regulated under statutes articulated in the Food, Drug, and Cosmetic (FD&C) Act and codified in 21 CFR 211 subpart E – i.e., the drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements. In addition, the regulation states that the container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.2
FDA’s expectation to support demonstration of CCI differs from that of other Regulatory Agencies. For example, while the European Medicines Agency (EMA) requires 100% CCIT of containers closed by fusion3, FDA recommends validating the manufacturing procedures to ensure maintenance of CCI1. FDA also recommends conducting CCIT in lieu of sterility annually and at expiry with a validated method able to detect breaches in the CCS and include a statistically appropriate number of samples.4 Documentation to support microbial integrity of the container closure should also include simulation of stresses from processing using the maximum exposure, sensitivity of the method, and demonstration of CCI over the shelf-life of the product.5
CCI failures can lead to DP sterility failures, change in product strength due to leaks, and may impact other product physicochemical attributes, for example cake hydration in lyophilized DP.6
Suitability of the container closure should be addressed during product development and should include a robust CCIT method appropriate to the type of container closure. Because the type of product determines the maximum allowable leak size, the method limit of detection (LOD) and positive controls should be product-specific. For sterile products, positive controls should be close to the microbial ingress LOD, which is about 20 μm7. Current expectations for new applications include demonstration of CCI using a validated method after worst-case manufacturing conditions, after secondary assembly and shipping of pre‑ filled syringes, and as part of the stability program.
FDA Case Studies
FDA Case-Study 1: Substandard Container Closure
Case-study 1 involves a lyophilized sterile DP for intravenous infusion. Soon after the application approval, the applicant reported multiple instances of defective glass vials and presence of particles from the vial and the stopper in the DP. Some of the defective vials were sent to a third-party contractor to assess the type of defects and their severity (Figure 1). Defects included deformation on the glass at the intersection with the stopper, glass particles attached to the internal surface of the vial, and airlines and cracks in the neck and the shoulder of the vials. The investigation concluded that the CCS (vials and stoppers) were of poor quality and that the quality of the DP could be impacted by a potential loss of DP sterility and presence of foreign matter in the product. Impact to patient safety would include infection, inflammation, immune response, and tissue damage8. The applicant resolved to select a different CCS.
The use of defective CCS has resulted in several voluntary recalls of sterile DP in the last 2 years. These recalls involved cracked vials at the rim and the bottom of the vial9,10, defective crimp caps with potential for CCI failure11, and multiple instances of presence of glass particles in the product12-17.
FDA Case-Study 2:
CCIT Not Suitable for Its Intended Use
Case-study 2 describes a pre‑ filled syringe (PFS) assembled with a finger flange and a plunger rod for sub-cutaneous administration. Manipulation of the CC during secondary assembly can impact the integrity of the primary CCS. Those manipulations include assembly of pre‑ filled syringes (PFS) into auto injectors, insertion of the plunger rod, needle safety device, etc. Although in-line controls during assembly operations may mitigate the risk of interactions impacting integrity of the CCS, integrity of the primary container closure should be demonstrated after secondary assembly.
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In case-study 2, the CCIT method selected to demonstrate integrity of the PFS after secondary assembly was the High Voltage Leak Detection (HVLD) test, which consists of placing the sample (CCS) under two electrodes that generate an electrical current. Integral samples do not conduct electricity; however, the resistance of the sample is reduced in the presence of a breached CCS with an electrically-conductive product, resulting in electricity being detected by one of the electrodes18. The HVLD test is able to detect breaches only if they result in a product leak at the time of the test6. However, breaches in the needle or the rigid needle shield area that can occur during secondary assembly of the pre‑ filled syringe cannot be detected by the HVLD method because these types of breaches do not result in product leakage. Another type of CCIT should be implemented to detect breaches that may occur during secondary assembly operations to ensure that the sterile CCS does not become exposed to the non-sterile environment. In case study 2, the applicant agreed during the application review period, to repeat the study with the blue dye ingress test.
Multiple lots of one DP ‑ filled in PFS were voluntarily recalled due to potential lack of sterility assurance, which was attributed to interactions between the product syringe and the tamper-evident container closure. Recalled PFS were shown to be microbially contaminated in subsequent testing of unrelease product.19
FDA Case-Study 3:
Inadequate Execution of the CCIT
Case-study 3 describes a lyophilized sterile product for intravenous administration that was tested for CCI using a blue-dye ingress test method. The method includes immersing vials in a dye solution under pressure and vacuum cycles. Vials containing blue dye at the end of the test are identified as breached.
However, in case-study 3, the tested vials were not reconstituted prior to inspection for blue dye ingress and therefore dye present in areas hidden from the observer (for example, under the vial caps) would not be detected. Reconstitution of the samples after the dye-ingress test would allow for detection of the blue dye in those hidden areas. During an inspection, the lack of detectability of the dye in the vials with lyophilized powder was presented to the manufacturing ‑ firm as an FDA-483 inspectional observation.
FDA Case-Study 4:
Inadequate CCIT Positive Controls
Adequate controls during method validation are intended to ensure that the method is suitable to detect breaches that may impact product quality and safety; inclusion of those controls during the routine CCIT will confirm the correct execution of the method.
FDA has assessed multiple applications with inadequate controls or lacking any CCIT controls. For example, in one application, the applicant included as a positive control a vial with a 26-Gauge needle inserted through the stopper. The internal diameter of a 26-G needle is 260 μm, and therefore does not ensure that the CCIT is able to detect breaches smaller than 260 μm. In another application, the positive control for a product in a PFS was a breached vial. The CCIT method (dye ingress test) used in this case included multiple vacuum and pressure cycles, which can have di erent impact on vials and syringes. PFS are susceptible to plunger movement during pressure differentials and a breached vial as a CCIT positive control for a PFS was not deemed an appropriate control.
In both cases described in case-study 4, the applicants agreed to conduct additional studies to identify adequate positive controls and to use those during routine testing.
FDA Case-Study 5:
Loss of CCI During Vial Crimping
Case-study 5 describes a liquid solution for intravenous infusion where DP vials were crimped with an aluminum seal after stoppering to provide a tight seal of the stopper and to maintain integrity of the CCS.
During crimping, forces are typically applied to the top and sides of the seal to exert pressure on the stopper and close the edge of the seal and maintain it in place (Figure 2). The pressure applied during crimping is critical, because excessive pressure may crack the vials and insufficient pressure may result in poorly sealed vials.20 Crimping parameters designed to maintain CCI are considered critical from a sterility assurance perspective and information and data demonstrating CCI after maximum and minimum crimping pressures is expected to be included in an application.
In this case, the product container closure was a 4-mL vial (4R) with a 13-mm stopper and a 13-mm aluminum seal with a flip-off cap. Crimping validation included CCIT on three different batches and 500 vials per batch. Eight vials were rejected (out of 11,161 ‑filled) from one of the batches (Batch 3) due to broken or cracked vials: three of the vials showed blue coloration after the dye-ingress CCIT, two vials had cracks in the base and the other had a crack in the neck under the crimping seal.
An extensive investigation was launched, and the root cause of the cracked vials was determined to be due to mechanical stress to the vials during the vial crimping process. The investigation revealed that the crimping equipment was not suitable for the intended CCS because the crimping head was a generic head used for 2-mL vials and these vials had a different angle at the lip than the 4R vials. In addition, Batch 3 (the batch with the cracked vials) used a new lot of aluminum seals that were slightly longer (0.06-0.09 mm) than the seals used for the other two batches. The combination of these two parameters (generic crimping head and longer seals) resulted in excessive pressure being applied against the vials leading to the vial cracking.
As a corrective measure, the applicant designed a new crimping head specific for the 4R vials. The new head had a smaller diameter than the generic head to resolve the variability in the seal length and the new head crimping angle was aligned with the 4R vial lip angle. The 4R crimping head was installed and crimping was validated with three consecutive water runs of 315, 315, and 500 vials. None of the samples were found cracked or showed blue coloration with the use of the newly installed crimping head.
FDA Case-Study 6:
Container Closure Integrity in Bags
Different regulatory agencies have different expectations when it comes to testing integrity of parenteral bags. EMA requires 100% CCIT in parenteral bags.3 FDA relies on a robust validation of CCI during the manufacturing process5 and on a risk assessment conducted by the applicant to determine the extent of CCIT during routine monitoring. Many products filled in bags are terminally sterilized and, as a result, pressure differentials generated during terminal sterilization could result in volume losses from breached bags which would be detected during the 100% visual inspection.
Case-study 6 describes a product sterile-filtered into fusion bags. CCI of the bags during sealing was validated by the vendor by applying pressure (6.0 psi) onto air-filled bags under water and detecting leaks visually (bubbles). The limit of detection of the method was 10 μm. However, CCI was not tested during routine manufacture or on stability.
During review of the application, it was noticed that one bag leaked during a media fill after incubation, and another leaked during shipping validation studies. Additional information from media fills revealed that up to 1.5% of the bags were filled but not incubated due to “potential of non-integral containers from a weakened primary container seal or damage to a primary container component. All leakers and any potential container integrity defects are not incubated.” The applicant indicated that bags with leaks would be identified during the 100% visual inspection. However, small leaks that could allow for microbial ingress may not be detected during visual inspection, resulting in an unmitigated risk to sterility assurance.
Leaks in fusion bags are not unusual. For example, a recent recall of 5% Dextrose for injection was conducted because of customer complaints reported that some containers were leaking, and, in some cases, visible particulate matter was present, which was identified as microbial contamination.21
Conclusion
Adequate container closure is critical for maintenance of quality and safety of parenteral drugs. Selection of the appropriate CCS and CCIT should be conducted during drug development stages. The CCIT should be suitable to the type of CCS, should include adequate controls, and a statistically significant number of tests samples.
Additional studies should be conducted during drug development and validation stages to establish the parameters to be used during manufacturing operations (terminal sterilization, filling, bag sealing, vial crimping, secondary assembly) and to ensure that those parameters will not compromise CCI. Controls during routine manufacturing and inclusion of CCI testing in the stability plan will ensure that a sterile product CCS is integral, and the product remains sterile during its shelf-life.
References
- FDA Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing, and Controls Documentation (May 1999)
- Code of Federal Regulations Title 21 Part 211 Subpart E §211.94
- EU GMP Annex 1 Revision: Manufacture of Sterile Medicinal Products (Draft)
- FDA Guidance for Industry on Container Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products (February 2008)
- Submission Documentation for sterilization Process Validation in Applications for Human and Veterinary Drug Products (November 1994)
- USP Chapter <1207>: Container Closure Integrity Testing
- Burrell, L.S. et al. Development of a Dye Ingress Method to Assess Container-Closure Integrity: Correlation to Microbial Ingress. PDA J Pharm Sci Technol, 54 (6), pp. 449-455
- Bukofzer et al. Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products. PDA J Pharm Sci Technol, 69 (1) (2015), pp. 123-139
- Hospira, Inc. voluntary recall; FDA announcement 3/5/2018
- Hospira, Inc. voluntary recall; FDA announcement 2/23/2018
- Endo Pharmaceuticals Inc. voluntary recall; FDA announcement 3/5/2018
- Hospira, Inc. voluntary recall; FDA Announcement 3/15/2019
- AuroMedics Pharma LLC voluntary recall; FDA Announcement 7/31/2018
- AuroMedics Pharma LLC voluntary recall; FDA Announcement 5/14/2018
- AuroMedics Pharma LLC voluntary recall; FDA Announcement 1/10/2018
- Fresenius Kabi USA, LLC voluntary recall; FDA Announcement 7/02/2018
- Hospira, Inc. voluntary recall; FDA Announcement 2/06/2018
- Darmgaard, R. et al. High-Voltage Leak Detection of a Parenteral Proteinaceous Solution Product Packaged in Form-Fill-Seal Plastic Laminate Bags. Part 1. Method Development and Validation. PDA J Pharm Sci Technol, 67 (6) (2013), pp. 634-651
- Premier Pharmacy Labs voluntary recall; FDA announcement 3/5/2018
- Mathaes, R. et al. Impact of Vial Capping on Residual Seal Force and Container Closure Integrity. PDA J Pharm Sci Technol, 70 (1) (2016), pp. 12-29
- Brawn Medical voluntary recall; FDA announcement 3/29/2019