Regulatory Considerations for introducing an alternative chromatography resin provider

In the ever-changing biopharmaceutical market, greater pressure is now being placed on manufacturers to improve their processes. Decades-old manufacturing techniques and technological advancements have triggered movement in the market towards more efficient and affordable processes from new providers. Biopharmaceutical manufacturing is subject to regulation from several authorities, all requiring notification of any changes to manufacturing processes.

This blog is a snippet from 'Resin Sourcing', an independent whitepaper co-authored by Brian Hubbard (CMC Bioprocessing Consulting LLC) and Duncan Low (Claymore BioPharm LLC) to help navigate the regulatory requirements of relevant authorities.


Click here to read their full paper on how to source a new chromatography resin supplier and see the full list of references used.
 

Extract from 'Resin Sourcing'

Risk Assessment


The first task in a science and risk-based process is to understand the risks associated with making the change (5), since the product may not be comparable after the change is made. This assessment should determine the effect the proposed changes have on the identity, strength, quality, purity and potency of a drug product or a biological product.

Generally speaking, upstream changes are more impactful than those made downstream, however there is the potential to impact size/structural variants of product and process related impurities (4). In the case of monoclonal antibodies, which are amenable to a platform approach (6), understanding and information developed from changes made to one process may (in certain cases) be used to support changes made to related processes (4).

Reporting Changes


Before embarking on process changes, it is important to determine the regulatory process and requirements for reporting the changes. The FDA uses three tier-based types of report (3, 7, 8):
  1. Prior approval supplement (PAS) - changes that have a substantial potential to have an adverse effect on product quality (i.e. major changes). Requires prior approval prior to distribution of product.
  2. Changes Being Effected in 30 days/ Changes Being Effected Supplements (CBE30/CBE) - changes that have a moderate potential to have an adverse effect on product quality (i.e. moderate changes)
  3. Annual report (AR) - changes that have a minimal potential to have an adverse effect on product quality (i.e. minor changes).
A 'new or revised purification process, including a change in a column' is given as an example of a change requiring a PAS (7). A more recent guidance for specific biologics (not including e.g. monoclonal antibodies for in vivo use and therapeutic recombinant-DNA derived products), it specifically cites a change in resin material as requiring a PAS (8).

In summary, a resin change would typically be viewed as requiring a PAS. Note that this could be relaxed to some extent based on discussion with the appropriate authorities and on the extent of the resin change (like-for-like, a minor change still functionally similar, or a different modality). A resin change to additional licensed molecules as part of a platform process, however, may only require a CBE30/CBE based on platform understanding and prior knowledge.

Assessment and implementation of changes


In general, the proposed changes must be assessed, documented and justified so that the company can demonstrate that it has sufficient knowledge to prepare and manage the impact of the change. This should be documented and provided to the relevant agency for approval prior to implementation. For a supplement (PAS, CBE30, or CBE) this includes:
  • A detailed description of, including a rationale for, the change
  • The product(s) involved
  • The manufacturing site(s) or area(s) affected
  • A description of the method(s) used, and the studies performed to evaluate the effects of the change on the product quality, and data derived from these studies (Comparability Protocol, CP)
  • Relevant validation protocols and data
  • A reference list of relevant standard operating procedures
 

Comparability Protocol


A comparability protocol is a comprehensive, prospectively written plan for assessing the effect of proposed CMC post-approval changes on the identity, strength, quality, purity and potency of a drug product or a biological product (i.e., product). It can be submitted prospectively with the original application or as part of the PAS. Approval of the original application containing the CP or a subsequent PAS containing the CP can provide an applicant with an agreed-upon plan to implement the specified changes, and in many cases, a justification to report the change(s) in a decreased reporting category (7, 8). The EMA also adopts a tiered approach to change (3, 9 - 11):
  • Type II - may have a significant impact on the quality, safety or efficacy of a medicinal product
  • Type IB - a minor variation, default if change does not fall into another category
  • Type IA, IAIN - no, or minimal impact

A 'substantial change' which 'may have a significant impact on the quality, safety or efficacy of a medicinal product' is listed as a Type II change, as is a change which may require assessment of 'comparability of a biological/immunological product' (9).

Post-Approval Change Management Protocol (PACMP)


The PACMP is similar in concept to the CP. It provides predictability and transparency regarding the requirements and studies needed to implement a change. It also requires approval be the regulatory authority, and the conditions and acceptance criteria outlined in the protocol must be met in order to implement the change (11).
  • Justification that there is a recognized future need
  • A detailed description of the proposed change
  • Risk assessment of the impact of the change
  • Discussion of the approved control strategy to identify and manage risks
  • Description of the studies to be performed, and the test methods
  • The approach to be used to demonstrate comparability
 

Quality by Design


Regulators have advocated the use of Quality by Design for the development and management of post-approval changes (12). A systematic approach to process characterization is taken, which begins with risk assessment and prioritization, process modeling and characterization and the setting of acceptance criteria. This leads to the development of a design space, within which satisfactory product quality is achieved (5, 12 - 15). Once established, this gives a manufacturer flexibility to make changes within the design space, since movement within an approved design space is not considered a change (from a regulatory filing perspective) (4, 16).

Risk Assessment


This assessment should identify the critical quality attributes (CQA's), the Key Process Parameters (KPP's) that are used to manage/control them, and downstream controls that can mitigate any limitations of a given unit operation of the process (e.g. removal of product or process related impurities).

In 2008, an initiative was taken by Subject Matter Experts (SME's) from several manufacturers to develop a case study (17) to advance the principles contained in ICH Q8 (R2), ICH Q9 and ICH Q10. The case study provides comprehensive guidelines on process development of a hypothetical antibody process in a Quality by Design framework. Specific details of both chromatography capture steps and purification steps are provided. This case study provides guidelines for the qualification of a scale down model, gives an approach to risk assessment of the steps (outlined in Figure 1), describes the design of multivariate and univariate studies, and reuse/resin lifetime studies.

The process is based on a three-step purification and also provides recommendations for changes to the affinity capture step (Protein A) and changing to alternative formats for anion exchange, and is further discussed in the section 'Technical Approach' (click here to read the full paper).


(Below) Figure 1: Risk Assessment approach used through A-MAb Development Life Cycle. Click the image to view the full figure.

Click the images below to enlarge.

ICH Q12


ICH Q12 is currently in draft form but reflects future thinking on change management as part of PLM (18). It is intended to promote innovation and continual improvement in the biopharmaceutical sector, and provides a framework to facilitate the management of post approval changes. Specifically, in certain ICH regions, it is 'not fully compatible with the established legal framework with regard to the use of explicity Established Conditions' (ECs) (18). ECs are legally binding information (or approved matters) as part of a filing that are considered necessary to assure product quality (18).

As a consequence, any change to ECs necessitates a submission to the regulatory authority. A decision tree for identification of ECs is given in (18), see figure 2, and examples of ECs are provided in (19). For a fuller discussion of the approach see the original documents.


(Above) Figure 2: Decision tree for identification of ECs (modified from ICH Q12). Click the image to view the full figure.
 

Identification of ECs


ICH Q12 discusses 3 alternative approaches that can be used separately or in combination to identify ECs:
  • A parameter-based approach, based on an understanding of the relationship between inputs and resulting quality attributes
  • An enhanced approach, with increased understanding of interaction between inputs, attributes and controls
  • A performance-based approach based on control of outputs rather than inputs
 

Revision of ECs


The options for revisions include post-approval submissions or through a Post-Approval Change Management Protocol (PACMP), filed either with the original application or as part of a post-approval regulatory submission. The PACMP should address the change in the context of the impact on ECs, bearing in mind ECs for a given unit operation may not be the same from one process to another. For example, a manufacturer may or may not make a claim for viral clearance for a Protein A step.

Making a change

It is now easier than ever for manufacturers to make a reliable and informed change to their manufacturing processes. Providing the simple regulatory requirements are met, manufacturers can achieve faster turnaround time on change implementation and begin to enjoy better productivity sooner.

Security of Supply


We understand that it can be difficult to breakaway from a longstanding supplier, which is why we introduced our dual-sourcing strategy to secure your supply of Protein A resin. We understand the concerns surrounding just one vendor with the capacity to supply to volumes of agarose-based resin required by the industry. That's why we opened one of the world's largest agarose manufacturing facilities, capable of meeting 30% of global demand. It aids in the production of our Praesto AP and APc resins, biosimilars to MabSelect SuRe LX and MabSelect SuRe respectively, with feedback from customers expressing comparable capabilities across multiple antibodies.

Would you like to speak to Purolite about an alternative supply of chromatography resins? Our Technical Specialists are always happy to discuss your options. Simply email us at lifesciences@purolite.com

References

Hubbard, B. & Low, D. (2019) Resin Sourcing p.1-6 https://www.purolite.com/dam/jcr:d0133f38-7cec-4850-96b0-29b1b1df01ae/resin%20sourcing.pdf