Raw Material Control for Biotechs (Part 2): Clinical Development Considerations 

Introduction 

This is part two of the Halloran Insights article on raw material control. Part one addressed the importance of establishing a level of raw material control at the earliest stages of product development. This article focuses on maturing the raw material control strategy in preparation for a commercial license application. The level of raw material control increases as clinical development progresses. This level of control is critical to achieving licensure of a therapeutic agent.  

As with part one in this series, the focus is on cell and gene therapies (CGTs). The actions described in this article generally apply to other types of early-stage biological therapies. 

Phases of Raw Material Control 

During phase one, clinical development quality assurance (QA) should review every Certificate of Analysis (CoA) associated with a raw material or consumable to confirm that the test results meet release requirements established by the manufacturer. If the raw material is derived from an animal source, then a Certificate of Origin (CoO) and TSE/BSE certificate should be obtained from the manufacturer. These certificates certify that the source material was obtained from healthy animals free of visual evidence of ill health. These certificates were described in part one of this series. 

During phase one clinical development, an identity test should be executed on every raw material used in the manufacturing process.¹ A routine method for assessing the identity of raw materials and consumables is Fourier Transform Infra-Red Spectroscopy (FTIR). The instrument is not expensive relative to other standard analytical instrumentation (i.e., Liquid and Gas chromatographs) and can be applied to a broad range of raw materials and consumables. In addition, extensive libraries of Infra-Red spectra are readily available to serve as reference spectra.  

For compendial grade raw materials, identity testing is described in the respective pharmacopeial chapter. An alternate test method can be used if the alternative method is fully validated, suitable for use, and gives equivalent or better results than the official USP method.² Evidence of this method validation must be available upon request and a summary may be provided to regulators to support the use of the alternate method.   

It is recommended that an appearance test for raw materials and consumables be executed upon receipt of the raw material or consumable that includes an inspection of the container/closure integrity and confirmation that the material meets the manufacturer’s acceptance criteria for product appearance (color, opacity, texture/form, etc.) Verifying container/closure integrity and appearance of the material is a valuable safeguard against using compromised materials and consumables in the manufacturing process. 

Consider using high quality raw materials at the outset of process development and certainly no later than phase one. Higher quality raw materials will typically cost more than research grade raw materials, sometimes substantially more. The use of research grade materials early in clinical development may make short-term economic sense but will not make long-term economic sense due to potential comparability concerns arising from the introduction of higher-grade raw materials later in clinical development. Therefore, whenever possible, replace Research Use Only (RUO) grade raw materials with higher-grade raw materials prior to launching clinical trials. Furthermore, to ensure comparability of pre-clinical drug product (DP) lots used in critical animal safety studies and clinical DP lots, it is best to make a critical raw material change before manufacture of DP for animal safety studies, thus mitigating potential FDA comparability concerns.³ 

Before delving into regulatory and quality expectations for later phase clinical programs, please note that an abbreviated or expedited clinical development program does not translate to an abbreviated or expedited chemistry, manufacturing, and controls (CMC) development plan. The same standards and expectations apply towards manufacturing a therapeutic agent regardless of a traditional or expedited clinical development pathway. In the case of an expedited clinical program, the impact of choosing research or non-pharma grade materials to manufacture clinical material could potentially compromise the license application. Selection of such raw materials should be discussed with the regulatory authority prior to implementation. Expedited clinical development programs require careful planning and alignment to ensure that CMC deliverables (including establishing a licensable raw material control program) are on track. In this author’s experience, early-stage biotechnology companies when planning phase three and licensure activities, consistently underestimate the time and cost required to address CMC gaps. 

Phase 2 Considerations for a Raw Materials Control Program  

Developing a raw materials control program for phase two requires considerable foresight and planning. 

Determine clinical supply requirements for phase two and phase three trials. This information will drive the planning effort for scaling up the manufacturing process to meet clinical demand. Supply chain considerations are a critical aspect of this planning effort. Some raw materials and consumables may have limited availability, and process scale-up demand could exceed supply. Identifying and qualifying one or, possibly, more back-up suppliers (discussed later in this article) could mitigate this risk. 

Establish an implementation plan for raw material changes having a potentially significant impact on the manufacturing process and DS/DP critical quality attributes (CQAs). Changes to CQAs are likely to trigger a formal comparability study.⁷ The change implementation plan should include a list of new reagents, solvents, auxiliary materials, biological raw materials, and starting materials to be used in production of phase two clinical trial material. The plan should describe CQAs for each material needed to ensure manufacture of phase two and phase three clinical trial material that is consistent or better than that used in previous stages of development. Some of the CQAs for the proposed new material may not be captured on the manufacturer’s CoA. In such cases the Investigational New Drug (IND) sponsor may have to establish them in process development.  

The plan to establish new CQAs should include: 

• Securing additional safety information for raw materials used in phase one manufacturing process⁸ (for example, novel excipients may have a safety profile that has not been fully established at phase one. That effort may extend into phase two and, possibly, phase three) 
• Replacing animal-derived raw materials with raw materials obtained from non-animal sources (if this is not an option, then develop a mitigation strategy to address possible introduction of adventitious agents into the manufacturing process stream. For example, it may prove necessary to modify the downstream purification process to include viral clearance and/or viral inactivation steps and demonstrate their effectiveness)⁴ 
• Evaluating compendial materials used in the manufacturing process, including excipients, to identify CQAs critical to the manufacturing process not described in the respective compendial chapter. In preparation for licensure, tests should be developed for these attributes and acceptance criteria established. This will be required by EU regulators when assessing Marketing Authorization Applications.⁵ These tests should be qualified in phase two and validated in phase three.⁶ Criteria for acceptance of these compendial materials in the manufacturing process will be evaluated by QA before the material can be released for GMP manufacture. The implementation plan should be launched prior to phase two and include a risk assessment to determine which process and raw material changes are most likely to trigger a comparability assessment. Any comparability assessment should be executed no later than phase two. Use of new suppliers/manufacturers should trigger vendor qualification no later than early phase two. 

Major changes to the manufacturing process in phase three are not recommended and, if comparability is not established, could introduce significant delays to the phase three clinical program and filing of the license application.  

During phase two, QA should begin to establish a robust vendor qualification program. If this program was launched for the phase one effort, prepare the program for the transition to phase three readiness (on site vendor audits, establishing a system for evaluating performance of raw materials from new suppliers when used in a pilot scale version of the manufacturing process, etc.) Assess the value of joining an organization that shares vendor audits, such as the Rx-360 consortium to supplement the audit program.^{9, 10}  

The raw materials acceptance and release program should be expanded now. A key feature of this program is the raw material specification document which describes lot release test and acceptance criteria used by the manufacturer of the material. It also includes certificates required from the manufacturer (Certificates of Analysis (CoA), Certificates of Origin (CoO), TSE/BSE certification, etc.) as well as the results from in-house testing for raw material appearance, identity, etc. QA will use this document to verify that an incoming lot of raw material meets all lot release criteria and is accompanied by all required certificates. Once this information is confirmed by QA, the raw material is released for use in GMP manufacturing. Raw material specification documents are controlled documents subject to change control. They must, at minimum, be reviewed and approved by QA. This documentation should be set up no later than early phase two to ensure proper control of the raw materials and consumables used in the GMP manufacturing process. 

Establish identity and appearance tests for every critical raw material prior to the launch of phase two, as noted earlier. As phase two matures, establish additional testing requirements for critical raw materials to document CQAs identified as indicators of raw material performance in the manufacturing process. These tests and acceptance criteria will be added to the appropriate raw material specification document and evaluated as part of raw material lot release. 

If a phase one/two clinical trial design is proposed, then recognize that the raw material control plan may require modification. Identify raw material changes that must be made prior to initiating the phase three clinical trial as well as those that are nice-to-have. If possible, the critical changes should be introduced during phase one/two to secure a patient safety read out prior to entering phase three. No later than early phase one, execute a risk assessment to identify those changes which pose the greatest risk of triggering a comparability assessment (i.e., changing to a different cell culture media formulation, changing excipients used in DP formulation, etc.) If any of the nice-to-have raw material changes fall into the high-risk category, then consider deferring them to post-license process development. For the critical raw material changes that must be implemented during phase one/two, the sponsor should plan to execute a comparability study in early/mid phase one using pilot scale manufactured DP incorporating all the raw material and manufacturing process changes that must be made. Comparability will be based on a comparison of CQA data and stability data between DP from this pilot lot and the phase one clinical trial DP. Allow at least six months to collect/evaluate the data and receive FDA input on the study protocol and report. This estimate factors in delays inherent in communicating with the agency. Bridging safety studies will be required if comparability is not established.  

Evaluate the quality of incoming plasticware used in the manufacturing process. QA should do this no later than phase two. Plasticware that comes into direct contact with the DS or DP manufacturing process stream is subject to specific quality requirements. The vendor for the plasticware should confirm that the source polymer used to manufacture the plasticware has been tested for bioreactivity and meets USP Class VI plastics standards.¹¹ Furthermore, the plasticware should have undergone an Extractables/Leachables (E&L) assessment.^12–15  

• The FDA expects that “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”¹⁶  

• EMA suggests “When single use equipment is used in evaluation studies, consideration should be given to leachables and extractables. Information should be provided on the nature and amount of potential leachables, and the removal of such impurities. Besides data, this normally includes a risk assessment.”¹⁷ 

If the polymer used to manufacture the plasticware contacts organic solvents at any point in the manufacturing process, then compatibility of that polymer with that solvent should be documented. Verify that, at the temperature of the process step(s) where plastic encounters solvent, compatibility is maintained. A polymer may have an acceptable leachables profile in the presence of a particular solvent at ambient temperature but not at elevated temperatures.  

If E&L study data is not available for a plasticware item that contacts the process stream, then execute a risk assessment to determine if an E&L study should be executed for that material. Many contract testing labs offer E&L testing services. All safety-related information for plasticware should be described in the raw material specification document. 

Identifying and qualifying back-up suppliers of critical raw materials requires significant time and effort. Therefore, it should be initiated in phase two. Supplier qualifications will include a QA qualification (paper audit or site audit for critical raw materials) and a CMC qualification. The CMC qualification entails an assessment of the CQAs of the back-up raw material to ensure it is of comparable quality to the primary raw material. This assessment should include an evaluation of each raw material manufacturing process, including the source materials used, critical raw materials used, lot release tests for each raw material as well as the acceptance criteria for each quality attribute. The impurity profiles of the primary and back-up raw materials should be comparable. Before locking-in the back-up suppliers, evaluate the performance of the back-up materials in pilot scale manufacturing runs. This pilot scale material should be subject to the full panel of lot release tests and meet all acceptance criteria. Product obtained from the pilot scale process should be placed on stability. 

If a contract manufacturer is responsible for qualifying raw materials suppliers and manages the raw materials program for your manufacturing process, confirm that they are verifying the quality of the raw materials used in the DS and DP manufacturing processes. This can be assessed by reviewing their process for receiving, inspecting, testing, releasing, and storing raw materials and consumables (and retains) for manufacture of DS and DP. This would typically take place during the contractor qualification audit. Bear in mind that, from the regulators’ perspective, the IND sponsor owns the manufacturing process, even if it is executed by a contractor.¹⁸ Therefore, it is advisable for the IND sponsor to review quality certificates for every raw material and consumable used by the contractor to manufacture DS or DP. Executed batch records should include this documentation which should be made available during batch record review. The client should not assume that the contractor’s raw material control program is flawless. In this author’s experience a contract manufacturer, claiming that the client’s manufacturing process did not use animal-derived raw materials, did, in fact, use animal-derived raw materials. The regulatory implications of such an error can be significant if identified by FDA during an IND or New Drug Application (NDA) or Biologics License Application (BLA) review. Therefore, a comprehensive evaluation of the contract manufacturer, including a thorough QA audit, is essential to ensure that these gaps are identified early and mitigated. 

Phase 3 Considerations for a Raw Materials Control Program  

Establishing a raw materials control program for phase three should focus on preparing that program for licensure. It should include:  

• Establishing and qualifying primary and secondary suppliers of critical raw materials and consumables. Qualification will include an evaluation that the manufacturer can consistently provide material meeting specifications and, for certain critical raw materials (i.e., cell culture media, novel excipients, etc.), a verification that the material, when used in the DS or DP manufacturing process, will result in product meeting lot release criteria. To achieve this, a complete analysis should be conducted on at least three batches before reducing in-house testing.^1,6 Full CoA testing of three lots of a raw material can take significant time. Identify and qualify a test lab with the requisite experience and regulatory/inspection history, as appropriate. Furthermore, tests for critical raw materials must be validated prior to licensure.⁶ These activities will consume months of effort and should be identified early and tracked in the project timeline.  

• Note that a manufacturer may produce only one or two lots of a particular raw material over a 12-month period. Work with manufacturers and suppliers to establish a schedule for receipt of qualifying material lots. Qualification of some suppliers based on testing three lots of a raw material may not be completed in phase three. For cutting edge CGT therapies or therapies for orphan indications, the raw materials may be too precious to qualify in this manner. These concerns should be raised with the FDA as early in phase three as possible. The agency may allow for some vendor qualification to be included as part of a post-licensure commitment.   

• Establishing a testing program, including a sampling plan, for bulk shipments of raw materials to the manufacturing facility. Phase three and commercial scale manufacturing will require large shipments of certain raw materials. For CGTs the largest deliveries will consist of cell culture media and, if used, serum supplement. Documentation of cold chain custody is critical for these shipments, including verification that the shippers used are qualified to hold temperature for the duration of transit time from shipping warehouse to manufacturing facility. A growth promotion test should be considered for every lot of culture media and serum supplement received as part of lot release for GMP manufacture. Growth promotion tests should be described in the raw material specification document used in the release process for these materials.  

• Critical raw materials like cell culture media and serum supplement may be routinely shipped at ambient temperature by the supplier. For manufacturing facilities located in warm, and possibly humid, climates there is a risk that these materials could be compromised by prolonged in-transit exposure to the environment. A growth promotion assessment of materials shipped under these conditions is highly recommended. If confronted by this situation, consider having these critical materials shipped under cold conditions. QA should confirm that cold chain custody will be maintained from warehouse to storage lockers at the manufacturing facility. 

• Maturing the raw materials receipt, inspection, and release program. All raw materials tests should be identified for all raw materials and validated in phase three. Sampling plans for incoming raw materials should be established. Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that considers the criticality of the material, material variability, past quality history of the supplier, and the quantity needed for analysis. Sampling should be conducted at defined locations within the container and by procedures designed to prevent contamination of the sampled material.¹ 

• Finalizing analytical procedures and acceptance criteria for evaluation of starting materials (vectors, cell lines, etc.) 

• Identifying changes in the manufacturing process and acceptance criteria for complex raw materials and starting materials. This new information should be submitted to FDA in an information amendment.⁸ 

• Addressing the need for executing a comparability assessment. Raw materials, solvents and reagents introduced in phase three should be accompanied by a risk assessment justifying why their inclusion in the manufacturing process should not trigger a comparability assessment. As noted earlier, it is highly recommended that no significant changes are made to the phase three manufacturing process. If these changes are unavoidable, refer to the FDA draft guidance on comparability assessment for human cell and gene therapies.⁷ However, be aware that FDA will expect to review and provide input on the comparability protocol and report. Both documents will be submitted as CMC amendments to the IND. This entails a chain of communication with the agency that could take six months or more, depending on the number and type of changes being considered and the results of the comparability study, before FDA determines if comparability has been demonstrated between products manufactured by the phase two and phase three processes. Comparability assessments executed in phase three are expensive and will have a significant impact on the project timeline. As noted earlier, if comparability is not demonstrated, then additional animal safety and clinical bridging studies will be required before the product can be considered for licensure. 

Conclusion 

This article has provided the framework for a raw material control program that can address the needs of each stage of clinical development. The reader is advised to be mindful of the quality and regulatory requirements for raw material control which will increase in scope and rigor as a company prepares for an NDA/BLA. 

References 

1. ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (2016) https://database.ich.org/sites/default/files/Q7%20Guideline.pdf 

2. https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practice-requirements-control-components-and-drug#2 

3. FDA expects that sponsors of INDs will assess comparability of DP used in preclinical safety studies (especially the GLP tox study) with DP manufactured for clinical administration. The comparability assessment typically compares the two DS and DP manufacturing processes, including the raw materials used in these processes, the tests employed to measure DS/DP CQAs, lot release criteria, DS and DP stability, etc. 

4. ICH Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin (1999). While this reference is directed at cell bank manufacture, the principles of viral clearance/inactivation apply to other manufacturing processes. 

https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf

5. European Medicines Agency (EMA). “Guideline on Excipients in the Dossier for Application for Marketing Application of a Medicinal Product.” 19 June 2007. “It may be necessary to add tests and acceptance criteria to the pharmacopeial specification, depending on the intended use of the excipient (functionality-related characteristics)” https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-excipients-dossier-application-marketing-authorisation-medicinal-product-revision-2_en.pdf 

6. PDA Technical Report No. 56 (revised 2016), “Application of Phase Appropriate Quality System and cGMP to the Development of Therapeutic Protein Drug Substance (API or Biological Active Substance). While protein therapeutics are the focus of this report, the raw material control discussion is directly applicable to cell and gene therapies. 

7. FDA Draft Guidance: Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products (2023). https://www.fda.gov/media/170198/download 

8. FDA Guidance: INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing and Controls Information (2003) https://www.fda.gov/media/70822/download 

9. https://rx-360.org/audit-program-overview 

10. “Raw material control strategies for bioprocesses”, G. Beck et al, BioProcess International, September 2009 https://www.casss.org/docs/default-source/cmc-strategy-forum-north-america/cmc-north-america-summary-papers/cmc-summary-paper-cmc-strategy-forum-north-america-winter-2009.pdf?sfvrsn=694b8792_3 

In 2009 the Rx-360 International Pharmaceutical Supply Chain Consortium was formed. Members include pharmaceutical, biotechnology and generic drug manufacturers along with suppliers, professional trade associations and regulatory agencies. The consortium’s mission is to “protect patient safety by sharing information and developing processes related to the integrity of the healthcare supply chain and the quality of its materials.” This organization offers members access to a library of audits for certain manufacturers and suppliers.  

11. USP<88> “Biological Reactivity Tests-In Vivo”, USP 42 NF 37 

12. Product Quality Research Institute Parenteral and Opthalmic Drug Product Leachables and Extractables Working Group Update: “Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular)” (09 September 2020) https://pqri.org/wp-content/uploads/2020/10/PQRI-PODP-Extractables-and-Leachables-Update_9Sept2020_FINAL.pdf 

13. BioPhorum Best Practices Guide for Extractables Testing of Polymeric Single-Use Components Used in Biopharmaceutical Manufacturing (April 2020) https://www.biophorum.com/wp-content/uploads/Best-practices-guide-for-extractables-testing-April-2020.pdf 

14. BioPhorum Best Practices for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing (July 2021) https://www.biophorum.com/download/best-practices-guide-for-evaluating-leachables-risk-from-polymeric-single-use-systems/ 

15. Extractables/Leachables standards have not been harmonized internationally as of December 2023. The International Conference on Harmonization (ICH) is developing ICH Q3E, a harmonized guidance for extractables and leachables. 

16. 21CFR 211.65(a) https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-D/section-211.65 

17. European Medicines Agency’s 2016 Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission, Section 6.1.3 https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-process-validation-manufacture-biotechnology-derived-active-substances-and-data-be-provided-regulatory-submission_en.pdf 

18. FDA Guidance: Contract Manufacturing Arrangements for Drugs: Quality Agreements (2016) www.fda.gov/media/86193/download