The biopharmaceutical industry uses many complex and innovative raw materials that, by definition, are not of a compendial status. Control of these raw materials is therefore defined by the license holder. Until very recently, this control was defined through the registration of the raw material supplier and part ID.
Even before the COVID-19 pandemic, this strategy was starting to put a strain on the supply chain, as it limited sourcing to a unique supplier and unique product. However, during and after the pandemic, this strategy has proven to be no longer valid if the industry wants to continue supplying patients with often life-saving medicines.
Remediation of the current inflexibility in the supply of process components and materials is a key industry priority and is linked to the registered details of products.
This article proposes a best practice approach to registering innovative and complex raw materials based on quality by design (QbD) principles. It can be applied to different families of non-compendial raw materials used when manufacturing biologics.
Guidelines And Regulations
Regulatory expectations for describing raw materials are covered in multiple guidelines depending on where and how they are used in the manufacturing process. For example, International Conference for Harmonisation (ICH) Q6B (Specifications: test procedures and acceptance criteria for biotechnological/biological products) contains requirements for raw materials and excipient specifications.
ICH Q11 (Development and manufacture of drug substances (chemical entities and biotechnological/ biological entities)) describes the regulatory expectations with regard to the selection of source and starting materials for biotechnological/biological drug substances. It introduces the definition of controls for materials but defers to ICH Q5A (for their viral safety), 5B (for cell lines), and 5C (for cell substrates) in terms of registration for biological products.
Finally, the ICH Common Technical Document M4Q (Quality) covers the minimum requirements for raw materials in a submission.
These documents set high-level expectations and their detailed implementation will vary.
When reviewing how materials are described in regulatory submissions, there are many practices.
As we have seen above, this is typically done by the material’s name and supplier for biopharmaceutical products, which means that alternative sourcing is complex. The typical strategy is revalidating the process with the new material, then notifying or submitting the change to the different regulatory authorities for approval. This can take up to several years for global implementations, creating delays and disruptions to the supply chain.
However, when the material is defined by its function and definition of its critical material attributes (CMAs), then the strategy becomes more flexible. This is not because it requires less scientific rigor to justify the change but because it does not require a regulatory authority’s prior approval before implementation, as per ICH Q12 (Technical and regulatory considerations for pharmaceutical product lifecycle management).
The definition of equivalency does not change with the proposal. The alternative material will be expected to fulfill the same predetermined criteria, could still require multiple batches, etc. The only change this proposal advocates is filing the materials in a manner that allows flexibility between materials fulfilling the same function with the same impact on product quality, safety, and efficacy defined by the same CMAs.
A CMA is defined in Understanding Pharmaceutical QbD as a “physical, chemical, biological, or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of that drug substance, excipient, or in-process material.”
The BioPhorum approach offers a simple and systematic process to identify these CMAs, based on QbD principles and consists of four steps:
- Define the target material profile (TMP).
- Describe the material attributes.
- Review the product summary control strategy.
- Identify the CMAs required to ensure product quality and safety.
It is then followed by the principle that a raw material is registered in submissions through its CMAs, to allow:
- increased flexibility of supply through a demonstrated understanding of those raw material attributes that are critical to product quality,
- enhanced quality of regulatory submissions, and
- potentially improved product and process robustness.
The approach allows raw materials to be defined through their CMAs that can be registered as part of the control strategy associated with raw materials and/or ECs. Its benefits include:
- increased flexibility of supply through enhanced knowledge and understanding of products and processes
- enhanced quality of regulatory submissions by demonstrating product and process knowledge and understanding
- improved product and process robustness through the definition and control of the CMAs.
There are also benefits for the agencies reviewing and approving manufacturing authorizations, such as:
- enhanced quality of regulatory submissions
- reduced number of notifications/supplements if the post-approval change can be documented in the biomanufacturer’s PQS or the Product Annual Report.
Step-By-Step Process Description
Step 1: Definition Of The TMP
In this approach, we define TMP as “a prospective summary of the characteristics of a material that ideally will be achieved to ensure desired drug substance and/or drug product quality and safety, and/or process performance. In other words: the description of the role to be fulfilled by the material.”
The TMP is built on:
- Intended use: definition of the role to be fulfilled by the material.
- Quality criteria: impact of the material on product quality and process performance.
- Safety criteria, e.g., the impact of potential contaminants that may harm the patient.
- Other requirements: typically desirable to ensure practical product manufacture.
Step 2: Description Of The Material Attributes
This involves understanding the different variables that characterize a material. These may comprise chemical attributes (e.g., material of construction), physical attributes (e.g., geometry), microbial attributes (e.g., sterility), and other safety attributes (e.g., impurities).
Step 3: Review The Product Control Strategy
In a QbD submission, product and process knowledge and understanding are summarized in the summary control strategy.
A control strategy is a prerequisite to this proposal because it describes how quality is built into the manufacturing process and how release testing is verification, rather than insurance, of product quality. It also describes the impact of process controls on downstream processing, thereby presenting a holistic approach to product quality.
Step 4: Definition Of The CMAs Required To Ensure Product Quality And Safety
The TMP, the material attributes, and the summary control strategy all help to understand what is important in the materials used in a specific process step and what can be defined as the raw material CMAs.
These are identified through a systematic review of the material attributes identified in Step 2, their impact on the TMP, and/or the product control strategy. The impact scoring is described as:
- Low Impact: Based on product and process knowledge and understanding, the attribute does not contribute to the TMP or the control strategy associated with the material and its use. No more characterization required.
- Medium Impact: Based on product and process knowledge and understanding, the attribute may contribute to the TMP or the control strategy associated with the material and its use. This attribute has an impact on product quality and process performance when combined with other attributes. A material attribute of medium impact may require controls.
- High Impact: Based on product and process knowledge and understanding, the attribute contributes directly to the TMP or the control strategy associated with the material and its use.
High-impact attributes are defined as CMAs. These require the definition of controls (appropriate limit, range, or distribution) to ensure the desired quality of output material. Neither the CMAs or limit, range, or distribution should change to demonstrate equivalency.
Medium-impact attributes are not defined as critical, but they require control as they may impact product quality and process performance when combined with other changes. They are typically part of preassessment or verification studies.
Strategy For Registration
When a marketing authorization holder elects to use this approach to define a raw material, Figure 1 provides recommendations on where the required information could be in the common technical document (CTD), depending on where and how the material is used.
Figure 1: Location of information relating to raw materials in the CTD
Established Conditions (ECs)
ICH Q12 defines ECs as legally binding information considered necessary to assure product quality. In that sense, CMAs are therefore defined as ECs for raw materials. A change to the defined ECs is considered a potential major change to product quality and therefore requires prior approval by regulatory authorities.
As per ICH Q12, a change to approved ECs is reported to the regulatory authorities through:
- Submission of an appropriate post-approval regulatory submission describing and justifying the proposed revision to the approved ECs. Justification may include information such as validation data and batch analyses.
- Submission of a post-approval change management protocol (PACMP) in the original marketing authorization application or as part of a post-approval submission, describing a revision to ECs or reporting categories and how the change will be justified and reported.
- Use of an approved post-approval regulatory commitment, as appropriate.
This process of prior approval is the one that causes extended timelines and disruption to the supply chain. However, if the ECs are not changed (e.g., the same CMAs are achieved by the two materials obtained from different sources), then prior approval is not required, as the change has no potential major impact on product quality, thereby allowing rapid implementation and flexibility of supply.
The approach does not provide a “free pass” for potentially major changes but allows license holders to focus on the areas that are critical to product quality through a risk-based approach. It also allows them to design powerful manufacturability studies, identify appropriate controls, and report their efforts primarily in their pharmaceutical quality system (PQS). When required, the change is reported in the Product Annual Report or a moderate change notification instead of a post-approval supplement that requires regulatory agencies’ review and approval before implementation.
Post-Approval Change Management Protocols
ICH Q12 also defines PACMPs as a tool to potentially minimize post-approval changes and their reporting categories.
PACMPs are reviewed and agreed upon with regulatory authorities as an appropriate means to demonstrate the absence of impact on product quality. The protocols and acceptance criteria are preapproved.
Therefore, they are particularly useful if raw materials have not been traditionally registered (through their suppliers and part IDs, for example). Or if the ECs are to be changed, they could reduce the change category from major to moderate, allowing a faster approval time, thereby limiting delays and disruptions to the supply chain.
This proposal is intended to start a transformational change in the registration of raw materials for the biologics industry. Implementing the recommendations is expected to bring a different approach to registering product control strategies, including CMAs.
This article is a summary of a recent BioPhorum publication on the topic. To read more, check out the full report in the BioPhorum approach to the registration of innovative raw materials using quality by design (QbD) principles. The paper includes how scoring of the impact of the change can be combined with variability and detection to define the criteria that need to be part of preassessment and verification studies. It also includes an Appendix where the approach is illustrated through the example of a viral filter used to manufacture monoclonal antibodies.