Strategic aspects of change control for pharmaceutical packaging systems

Since leachables may impact the dosage form’s suitability for use, packaging systems and packaged dosages forms are qualified to establish their suitability, and such qualifications are required parts of regulatory submissions. These qualifications remain relevant to approved and marketed packaged dosage forms until changes are made to their packaging – a frequent occurrence in the pharmaceutical marketplace. When packaging changes occur, suitability for use must be re-assessed. This article considers certain strategic aspects of change control, specifically focusing on patient safety impacts.

Introduction

Plastic materials are widely used in pharmaceutical packaging systems. Interactions between plastic packaging systems and their contained dosage forms such as leaching, the release of entities in the plastic material to the packaged dosage form, are well documented.^1-8 Leaching can affect the quality, efficacy and safe use of the packaged dosage form, as foreign leachable impurities can be undesirable due to their chemical or physical nature, reactivity and/or toxicity.  

During development, the packaging system is characterised for its propensity to contribute leachables to the packaged dosage form under typical or simulated use conditions. Establishing a packaging system’s suitability for use via a complete and appropriately rigorous extractables and/or leachables assessment is a universal requirement in regulatory submissions involving either the packaging system and/or packaged dosage form.^9,10

Once a pharmaceutical product consisting of a dosage form and its packaging has been accepted as suitable for use by the relevant regulatory authority, the product’s extractables/leachables assessment remains appropriate and applicable throughout the lifetime of the product, barring significant changes to either the dosage form or its packaging. Although there are compelling reasons to minimise changes to an approved packaging system and/or its materials of construction, it is an unfortunate reality in the pharmaceutical industry that packaging systems and their materials of construction are changed with inopportune frequency. Thus, exercising change control is an ongoing challenge in ensuring that an approved pharmaceutical product or packaging system has an appropriately long market lifetime.

This article considers strategic aspects of change control for pharmaceutical packaging systems, specifically focusing on the impact of changes on patient safety.

Change control versus initial registration

An extractables/leachables assessment performed for registering a pharmaceutical dosage form and/or packaging must be sufficiently complete and rigorous that it unambiguously establishes the suitability for use of the dosage form and/or package. As the burden of proof for suitability is substantial, the suitability assessment involves considerable data generation and analysis.

Change control is potentially quite different from initial registration, as a change occurs after the initial registration has been secured. A change is made to a packaging system that has already been established as being suited for use, meaning that the question to be addressed in change control is not necessarily, ‘is the changed packaging system suited for its intended use?’, but rather, ‘how does changing the packaging affect its suitability?’ This distinction is important because it raises the possibility that change control testing could be less extensive than the testing required for initial registration. That is, the effort required to establish ‘relative’ suitability (ie, no change in suitability) may be considerably less than the effort to establish ‘absolute’ suitability (ie, that the system is suitable).     

Material versus system changes

In certain respects, all changes are system changes and a change assessment that involves testing the changed packaging system is always the most definitive way to address an alteration. However, testing the changed packaging system may not be the most practical and economic approach to change control, especially for those changes that can be understood, assessed and addressed at the material level. 

While all changes are system changes, some are more specifically material changes, such as those made to a system’s material of construction or to the system’s materials of construction. For example, changing a material’s additive package is a change in a material. But changing the vendor of a polypropylene resin used in a packaging system is a change of a system’s materials. 

Alternatively, certain system changes are not also material changes. For example, any change in the configuration of a system, such as changing the relative thicknesses of layers in a multi-layered film, is a change that is not material-based. Other examples include: changing the processing of materials into the finished systems; changing the dose or type or conditions of system sterilisation; adding, removing or modifying washing or rinsing steps; and re-locating the manufacturing site.

Clearly, system changes that are also material changes could be properly assessed at the material, versus the system, level. This is important as the change assessment performed on a material may be more simple, or less expensive, than an assessment performed on the entire system.

Impact assessment

The spectrum of assessments that could be performed for change control span the range from no testing to a complete re-do of the registration suitability assessment, with many possible variations in between. As it is logical that the magnitude of change assessment is directly related to the impact that the change could have on suitability for use, it is also logical that the first step in change control assessment is performing an impact assessment to establish the potential consequence of the change. This impact assessment essentially differentiates inconsequential changes (those that require little or no change assessment) from those that require a more extensive change assessment. To achieve this, it considers two aspects of the change – magnitude and potential effect. If the magnitude of the change and/or the potential effect of that change is larger, the potential consequences are more significant, and more rigour is required in the change assessment.

It is interesting to contrast the level of effort expended in the impact assessment compared to the level of effort expended in the change assessment. For example, impact assessments required at the extremes of the change assessment spectrum are often trivial, as the circumstances that require extreme change assessments (either no testing or a complete re-do) are more or less ‘obvious’. For instance, completely redoing the extractables/leachables assessment performed for registration for change control would only be required in those circumstances where it is obvious that the change is likely to be consequential. As an example, consider a change that involves a new vendor of a primary additive of unspecified purity that makes up roughly 30% by weight of a ‘one plastic’ container for solution drug products. Because this is obviously a large change, the impact assessment would be simple and straightforward.

Similarly, an impact assessment that supports no testing would also be simple and straightforward, as it is ‘obvious’ that such a change must be inconsequential. For instance, consider changing the vendor of a well-characterised, high purity (98% or better) secondary additive that is present at a level of 0.1% in a minor plastic (less than 5% of the container weight) used in a multi-layered container for solution drug products. If the impurities in the secondary additive are unspecified, then the suitability risk associated with the change depends on the nature of the impurities and would be greatest if there was only one impurity. For a container weighing 10g, the total amount of such an impurity in a container would be 10µg. Based solely on this simple and straightforward impact assessment, it may be possible to conclude that the suitability impact of this small change would be inconsequential.

If all changes were as straightforward as these examples, then change control assessment would be an uncomplicated process. Unfortunately, considerable and highly detailed information is typically required to perform a proper impact assessment. The benefit of collecting such information depends on the probable outcome of the assessment. If a complete re-do is likely to be required, then it may be more practical and efficient to produce an assessment as simple as ‘insufficient information to assess, perform a redo’, as opposed to performing a rigorous one.

Perhaps, however, the value of a rigorous impact assessment lies in its ability to focus the change assessment. For example, it may be sufficiently rigorous that it concludes that the suitability risk is limited to a small number of specified extractables, as opposed to either all or unspecified extractables. In this case, the redo required by the impact assessment would not be a complete redo, but rather one that focuses only on these targeted extractables. Combining a rigorous assessment with a targeted re-do assessment may be more practical than the combination of a less rigorous one and a screening-type re-do assessment.

Material changes, focusing on safety

A rigorous and proper impact assessment is information-based and not inference-based. Thus, the most significant action taken in impact assessment is identification and procurement of the required critical information. Given the myriad changes that can be envisioned for pharmaceutical packaging systems, it is challenging to provide general suggestions as to what is critical information. However, a specific change situation can be more rigorously addressed. To illustrate, consider the patient safety impact of changing an individual construction material for a marketed packaging system. The impact assessment must establish the magnitude of this change and its possible effect. To establish the magnitude, one must quantitatively define the nature and extent of the change and the extent to which the patient is exposed to it. Information required includes:

1. A detailed and quantitative description of what has, and has not, changed about the material.
2. All available test data related to the composition or chemical nature of the changed material.
3. A detailed and quantitative description of the packaging system, specifically establishing the material’s place in, and contribution to, the system.
4. A detailed and quantitative description of the clinical use of the packaged dosage form.

Armed with sufficient information associated with these items, the patient’s clinical exposure to the change can be established. Although items 1, 3 and 4 are self-evident, item 2 is less clear and relevant information for this item may vary from change to change. For example, consider a material that is being changed by adding a new antioxidant. If the material’s vendor has performed migration studies for the new addition, then this information could be relevant to the impact assessment (as the migration rate could impact the magnitude of patient exposure).

Considering the case of moving a material’s manufacturing from one plant to another, a critical piece of information would be whether the ingredients used by both plants are the same. It is critical to ensure that the ingredients are both the same chemicals and have the same source, as the same chemicals from different sources may have different properties and impurity profiles (and thus potentially different effects).  

If such a magnitude assessment establishes a patient’s exposure to specific substances, then the effect assessment involves toxicological safety assessment of those substances. If such a magnitude assessment establishes patient exposure to unspecified substances, then the effect assessment could involve toxicological safety assessment using threshold concepts such as the analytical evaluation threshold (AET)¹¹, safety concern threshold (SCT)¹¹, or staged threshold of toxicological concern (TTC).¹²

In some changes the magnitude assessment cannot provide clarity in terms of patient exposure to specified or unspecified substances. It may still be possible to perform an effect assessment for such changes; however, it would need to be based on information which attests to the likely safety of the changed material. For example, if it has been established that the changed material meets its relevant compendial requirements, then this could indicate that the changed material is safe, as compendial requirements are presumably in place to ensure that safe materials are used in packaging. If, for example, the changed material was a polypropylene, the ability of the changed polypropylene to meet the specifications contained in USP monograph <661.1>¹³, or in Pharm Eur monograph 3.1.6¹⁴, provides some assurance that the changed material is appropriate to use in a packaging system.

Additional information which could be used to infer the safety of a changed material include, but are not necessarily limited to:

1. Certification concerning the changed article’s status with respect to indirect food additive regulations.
2. Certifications related to regulatory or company restrictions on composition (eg, Registration, Evaluation, Authorisation and Restriction of Chemicals [REACH] certification, company ban on the use of certain chemicals).
3. Material safety data sheet (MSDS) for the changed article.

Outcomes of the impact assessment

Impact assessments can have four outcomes:

1. The information secured is insufficient to establish that the change is inconsequential. In this case the change owner can either secure additional information (thereby continuing the assessment) or end the assessment by concluding that the change is potentially consequential and that further testing and change assessment is required.
2. The information secured is sufficient to establish that the change is inconsequential, in which case the change assessment is complete and the change is approved.
3. The information secured is sufficient to establish that the change is potentially consequential, in which case further testing and change assessment is required.
4. The information secured is sufficient to establish that the change is adversely consequential, in which case the change is rejected.

Conclusion

Changes to approved/marketed packaging systems are unavoidable in the pharmaceutical industry. Such changes are managed by a process termed change control. Although the considerable variation in possible changes adds uncertainty to change control, certain aspects are straightforward to define and address. For example, all changes must be assessed for impact, where the impact depends on the magnitude of the change and its effect. Furthermore, the desired outcome of the assessment is that the change is inconsequential, as it is desirable that changes be implemented (versus being rejected). Moreover, it would be difficult to implement a change that had a consequential effect on the packaging system, the packaged dosage form or the dosage form user. As these aspects of change control are well-defined, the uncertainty in change control revolves around establishing, procuring and assessing the information that is necessary to produce and justify the conclusion that the change is either consequential or inconsequential.

It is appropriate to suggest that most information required to perform an impact assessment would be provided by the change agent, which for material changes is either the material’s vendor or the material’s user. Testing of the changed materials and/or changed packaging system is required to fill gaps in the information required for the impact assessment. If there are no information gaps, no testing is performed at this stage. Furthermore, when a change has been impact assessed as potentially consequential, testing may be required to more clearly define the actual consequence. The larger the potential consequence (due to either the magnitude of the change or its likely effect), the greater the amount or the rigour of the testing required. However, in most cases the testing required to fully assess a change is less, in scope or in rigour, than the testing required to register the packaging system in the first place.

Change control which balances information collection with testing, as well as the amount and type of information required, with the perceived consequence associated with change is most likely effective and efficient.

Biography

DR. DENNIS JENKE is a Distinguished Scientist at Baxter Healthcare Corporation, where his primary responsibility includes the assessment of material/product compatibility, specifically establishing the suitability for use of packaging systems, manufacturing systems and administration devices for pharmaceutical products (ie, leachables/extractables). He has published extensively in the areas of analytical chemistry, environmental science and material/solution compatibility and serves as an expert reviewer for numerous pharmaceutical and analytical journals. He is the author of Compatibility of Pharmaceutical Solutions and Contact Materials, Safety Considerations Associated with Extractables and Leachables, and a contributing author to the Leachables and Extractables Handbook. Dr. Jenke is a member of numerous industry groups whose charter is to establish best demonstrated practices in the area of material/solution compatibility. Dr Jenke can be contacted at [email protected].

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