1. Introduction
Container closure integrity (CCI) is the ability of a container closure system to maintain the sterility and product quality of sterile final pharmaceutical, biological, and vaccine products throughout their shelf-life.
It is a regulatory requirement that the design of a container closure system be qualified. There are multiple methods available to qualify the effectiveness of a selected container closure system as detailed in industry guidance and literature. Selection of an appropriate method is based on the container closure system to be qualified and its contents. The normal variation within the manufacturing process should be taken into consideration when qualifying the integrity of the closure system.
While the regulatory expectations and industry standard practices for initial CCI qualification are well defined, the regulatory requirements with respect to in-process or routine manufacturing remain unclear with the exception of fused containers.
This paper addresses the benefits and challenges of CCI testing (CCIT), the importance of process control and in-process testing to ensure product quality, as well as circumstances under which 100% integrity testing during routine manufacturing should be considered. The scope of this paper includes drug product manufacturing of sterile injectable products, including vials, syringes, bags for intravenous application, and inhalation products, but not products compounded in pharmacies.
2. Establishing Process Control: A Holistic Approach
Demonstration of CCI is required throughout the lifecycle of a sterile pharmaceutical product, assuring integrity of the closure system through to its expiration date.
During the development stage, the qualification of the container closure system is commonly performed. Validated CCIT methods such as helium testing, microbial or dye ingress testing, or vacuum decay testing are selected as appropriate depending on the product, the closure system, and the production environment being evaluated. The qualification of the container closure system can include such strategies as challenges with worst-case critical dimensions, or confirmation of critical process controls such as min/max sealing ranges, min/max line speeds, etc.
Regulatory documents are clear on the requirement that all containers that are fused on the filling line require 100% integrity testing. For all other containers with well-characterised manufacturing processes and controlled container dimensions, in-process integrity testing or release testing is not a regulatory requirement. A well characterized and controlled process should consist of a qualified container closure system with effective, monitored process controls in place to assure the maintenance of the process specifications required to produce integral container closure systems. With robust process controls in place, 100% integrity testing may not be required. Controls may include establishing specifications for incoming components, qualification of manufacturing equipment including a qualified vision inspection system, and statistical sampling strategies combined with off-line testing.
Establishing Specifications
Package development includes the design and selection of container components such as vials, stoppers, and seals based on design verification, proper matching between components, and proven history. Component vendors have quality systems in place to ensure vendor production processes meet standards and demonstrate the capability to repeatedly manufacture components well within the agreed-upon specification limits. The control of incoming components is critical for the ongoing assurance of product quality and container closure system integrity. Pharmaceutical manufacturers typically have vendor qualification programs, incoming quality checks, and controls in place, which can include dimensional and material verification and automatic or manual visual verifications.
Critical dimensions of container closure system are defined and specified in the supplier's CofAs and further confirmed in the installation qualification/operational qualification (IQ/OQ) testing of filling equipment including a proper review of the supplier qualification and process capabilities. When deemed necessary, additional testing, such as visual inspection, can also be applied to incoming component lots to detect potential batch defects or identify trends that could impact closure integrity. The sample size for incoming quality control test would be determined per sampling statistical justification, for example, using the ANSI/ASQ Z1.4-2008 or ISO-2859. Change control is an inherent part of the component quality system and critical to the maintenance of the qualified state of the container closure system.
Qualification of Manufacturing Equipment and Ongoing Manufacturing Process Controls
CCI is demonstrated in design and established ranges are then verified in production. Qualification is required for every element of a process. This includes equipment and installation qualification, the qualification of process variables (e.g., environmental and processing extremes such as temperature or time), as well as those elements of manufacturing that could potentially affect the materials or process such as washing, sterilization, depyrogenation, or siliconisation.
For example, on a vial capping machine, the top and bottom spring sealing force required for robust seals should be qualified at worst-case conditions, from washing and sterilization, through sealing including line speeds and temperature exposure. Manufacturing process controls such as qualifying the capping force to be used in manufacturing is part of a further verification of the ranges established in the design stage. The correlation between capping force and CCI ranges should be established. Location of capping seal rails set points, and 100% raised stopper detection, are also examples of process controls that can be applied.
All finished product is 100% inspected for critical defects. Camera/light-emitting diode (LED) systems may be employed as an additional tool providing a 100% process control to detect obvious artefacts such as raised/missed stoppers, or wrong placement of components that potentially could affect the integrity of the container system.
Control limits may be applied to either inform adjustment of parameters during production, in follow-up of reject rates, or applied in trend analysis both intra- and inter-batch. Control charts may also be useful in production checks whereby if anomalies are found, control charts and or trending can aid in the identification of root cause(s).
Statistical Sampling:
During qualification activities (e.g., scale-up batches or start-up), performance of CCIT using a statistical sampling plan is one tool that can be used to provide additional data about the manufacturing process.
Once system suitability is demonstrated, the manufacturing process is qualified, and ongoing process controls are in place, the process capability should be established to ensure the process will not create defects and is compatible with the performance of the qualified inspection techniques. Establishment of process capability avoids a process that “inspects into quality”.
In the cases where container defects cannot be clearly detected by typical in-line inspection techniques (such as vision inspection), a possible approach to managing any risk could include the addition of at-line CCI verification using a statistical sampling plan. When applicable, at-line CCI verification can allow detection of process/equipment related irregularities in real time, and helps identify which part of the production is affected and should be discarded to ensure there is no risk for the patients.
Summary of Manufacturing Process Control
Confidence in a manufacturing process and the ability to repeatedly produce integral container closure systems must be evaluated in a holistic manner. This includes
Establishment of vendor process standards, specifications, and capability
Quality control of incoming components for assessment of critical attributes
Qualification testing of components which may include utilizing worst-case combinations
Qualification of manufacturing equipment and establishment of process capability
100% visual inspection to remove components with defects which could affect CCI
Control charts and or trending can aid in the identification of root cause(s)
This may also include as applicable:
In-line vision systems for detection of irregularities in the process
Application of statistical sampling strategies in combination with at-line CCIT.
These provide a robust indication of the status of a manufacturing process including the maintenance of the container closure system. Additionally, a further assurance is provided as part of shelf-life stability assessments.
Shelf-life Stability through Expiry
The shelf-life determines that stability-indicating quality attributes do not change significantly during the period of time when the product is manufactured, stored, transported, and finally used.
For the manufacturers of pharmaceuticals, vaccines and biologics a critical safety attribute is sterility and its maintenance through the product life cycle.
Sterility testing has been used to demonstrate product sterility at release and product expiry. However, sterility testing is generally not considered to be a test of the closure integrity, but to confirm the aseptic condition of the product throughout the aseptic filling process and storage. Regulatory guidance recommends that CCIT can be performed in lieu of sterility testing to assure the sterility of the product though shelf-life (1). Implementation of a validated physical, chemical, or microbial CCIT method as part of the routine stability program provides an additional assurance that integrity of the container closure system is maintained throughout shelf-life, through expiry and has been widely implemented in the pharmaceutical industry.
3. Points To Consider In Applying 100% Integrity Testing
The primary aim of developing robust processes and testing of pharmaceutical, biological, or vaccine products is to ensure product quality. One hundred percent testing implies that testing is applied to each and every unit produced in a batch and not just a statistically representative sample from a lot or batch.
During routine manufacturing, CCIT is commonly replaced with process (or in-process) checks. Multiple checks on product-filled samples are required to provide confidence and evidence that processes are effectively controlled. It is generally recognised that 100% integrity testing is required for certain types of products. Containers that are sealed by fusion on the filling line require 100% leak testing. It is, however, unlikely that a well-controlled process, as described in previous paragraphs, would require 100% integrity testing on release.
During routine production, however, various scenarios and events may arise that can adversely affect the seal. Such events, though rare, fall outside of the scope of qualification, and thus increase the value derived from 100% testing. In these scenarios, a risk assessment can be employed to determine if such an application would be valuable.
Real examples from across the biopharmaceutical industry demonstrate that such occurrences do occur, and in those instances industry has responded with solutions involving 100% testing. Some examples are provided below:
Case I: A robust, well-characterized process/product exhibits sealing issues that are linked to inconsistency of incoming component lots. Although qualification provided confidence in the process to the limits of equipment's capability, an issue so rare would not be captured during qualification. Stability testing would also have proved ineffective in identifying this issue One outcome was the implementation of 100% headspace integrity testing as an additional check to identify and reduce lot-to-lot component variability.
Case II: A well-characterised process/product exhibits sealing issues that are linked to siliconisation of stoppers from a given vendor. The issue leads to stoppers that are unable to move freely through the equipment guides and subsequently are not correctly positioned in the vials, potentially leading to integrity issues. A high-voltage leak tester was installed at the point of closure to check the closure of every individual vial.
Under circumstances where 100% integrity is warranted, there is no formal process for establishing yes/no decision on 100% testing. Each product and process is evaluated on a case-by-case basis, based on specific knowledge of the product and/or process.
Some manufacturers perform a systematic risk assessment or quality-by-design appraisal, to identify potential areas of risk and establish process controls and the type of equipment potentially required for all new products. The aim of such assessments is to pre-empt issues and ensure the necessary controls, budgets, and equipment are in place to prevent them from happening.
4. Options for 100% Integrity Testing
Equipment or component variations can lead to defects if not fully controlled. If more stringent controls, such as those listed above, are not practical or possible, then additional 100% checks are required to provide the greatest levels of confidence in manufacturing processes.
Technology is currently limiting. If a flexible technological solution would exist that could rapidly inspect every vial, syringe, cartridge, bottle, device, and so on whether filled under inert atmosphere, or vacuum, or neither and give a yes/no answer on each unit, then confidence could be claimed in the processes well beyond the current limits.
USP 1207 as well as PDA Technical Report 27 provide a comprehensive list of potential 100% integrity test methods; the list will not be repeated in this paper. Each test method requires that it be properly evaluated and validated for the application, including not only the container closure system but also the impact to the product. Selection of a 100% integrity test must be “fit for use”, evaluating the process, product, and container closure system. Examples include devices such as autoinjectors or those with safety devices that provide additional complexity in selection of a 100% integrity test method.
5. Conclusions
Performing 100% CCIT does not provide certainty that a process is well controlled, and moreover implementation is not always possible due to the nature and construction of the container. Conversely, building confidence into a process by component/equipment qualification, tight definition of specification ranges for container closure critical attributes, incoming inspection of component critical attributes, and the use of in-line detection techniques (such as raised stopper detection) to identify artefacts removes the need for 100% integrity testing.
One hundred percent integrity testing introduces an additional step that is not always necessary, and not always suitable for the high processing speeds in the industry. Indeed, many companies retain process-related data that, in the spirit of concepts like quality by design, do not advocate 100% testing but, instead, use other controls to reduce testing. By remaining vigilant, the biopharmaceutical industry is able to ensure quality and respond quickly and appropriately when issues do arise.
The wide variety of dosage forms currently produced also raises questions around the applicability of 100% integrity testing. There is no single solution that is applicable across all dosage forms and production types. Additionally, advances in processing technology are not always matched by advances in testing capability. Many integrity test methods do not apply to modern products, such as pre-filled devices which may have large “dead-spaces” that make many existing test methods obsolete. There is no “one size fits all” (or even “fits most”) solution or method: Trying to fit appropriate technologies to processes and products remains a challenge.
When warranted, 100% in-process testing may be required. Each product and container closure system including its manufacturing process must be assessed to determine risk to the integrity of the system. Risk versus benefit must be evaluated, and the application of the technology must be determined on a case-by-case basis.
A practical, and justifiable, position is to build closure integrity into processes. When critical-to-quality parameters are assessed and controlled during the development and qualification phases, with on-going monitoring as well as at-release and stability, issues can be averted, or mitigated. One hundred percent CCIT is one possible tool that can be applied to provide additional assurance for some products, but challenges currently exist in its application.
The future holds the potential to implement such technologies in the CCIT and in-process space. Working together to design a roadmap for suppliers will facilitate and, importantly, accelerate filling the gaps, leading to solutions that are geared towards industry's real-life needs and speeds, without compromising the business viability.
6. Related Documents
CFR 211.94(b) Drug Product Containers and Closures.
Eudralex Part 2, 9.20.
PDA Technical Report 27. Pharmaceutical Package Integrity, 1998.
International Conference on Harmonization (ICH) Guidance Q1A (R2) Stability Testing of New Drug Substances and Products, 06 Feb 2003.
International Conference on Harmonization (ICH) Guidance Q5C Quality of Biotechnological/Biological Products, 30Nov1995.
FDA Guidance for Industry: Container and Closure Integrity Testing in lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products, February 2008.
EU Annex 1.117, 01 Mar 2009—Manufacture of Sterile Medicinal Products.
PIC/S Annex 1.117, 01 Jan 2013 Guide to Good Manufacturing Practice for Medicinal Products.
CPGM 7356.002A, FDA Compliance Program Guidance Manual, Sterile Drug Process Inspections, Nov. 2012.
USP 36-NF31 Annual Chapters <1207> Sterile Product Packaging—Integrity Evaluation.
EU Annex 1.123, 01 Mar 2009—Manufacture of Sterile Medicinal Products.
Footnotes
BPOG SPECIAL SECTION: The following article is a special editorial contribution from the BioPhorum Operations Group (BPOG). Please note that it did not go through the PDA Journal and Pharmaceutical Science and Technology regular peer review process.
- © PDA, Inc. 2015
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