Fast-Tracking Drug Development: How Science, Strategy, and Structure Enabled Rapid CMC Success
This article presents experiences from seven recent accelerated development program case studies. These experiences provide insights that could help companies progressing through accelerated development programs for products meeting unmet medical needs or significant therapeutic needs, such as those with anticipated Breakthrough Therapy (United States) or PRIME (European Union) designation.
The main findings indicate that companies are increasingly adopting alternative science- and risk-based approaches in regulatory submissions, driven by growing regulatory acceptance. These approaches include greater use of prior knowledge from product development and similar products or processes in the control strategy–often referred to as platform technology. Additionally, modeling of processes, stability, and biopharmaceutics is being utilized in parallel with changes in the regulatory landscape.
These alternative approaches can accelerate development while mitigating project and technical risks. A key point of emphasis is the importance of early engagement with regulatory agencies to discuss the use of these alternative approaches to expedite product development. Such proactive communication helps align development strategies with regulatory expectations, streamlining the approval process and increasing the likelihood of regulatory success and earlier product launch.
Introduction
Formal regulatory pathways for accelerated development programs have been available for over a decade.1, 2. These pathways are generally driven by encouraging early phase clinical data that can put chemistry, manufacturing, and controls (CMC) data on the critical path for the product marketing authorization (MA). Therefore, innovative CMC tools are needed to meet clinical development timelines for regulatory submission.
Previous articles by ISPE3, 4, 5 and the European Association of Industries and Associations (EFPIA)6 have discussed challenges in meeting regulatory expectations for the CMC section of MAs for accelerated development programs. These previous articles stressed that regulatory approaches were evolving rapidly, and industry experience was increasing, particularly because of the COVID-19 pandemic and the need for rapid development and supply of vaccines and treatments.
Even prior to the pandemic, agencies and industry were discussing the means to accelerate quality product development according to medical needs. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) held workshops on prior knowledge and tools to speed up CMC product development. The EMA also began a Quality Innovations Group program of discussions with industry stakeholders. The pandemic put these acceleration ideas into the forefront of pharmaceutical development strategy.
The authors of this article have collected case study information on approaches used for products under accelerated development programs. The products in these case studies have been approved for use by patients, some initially under emergency use authorization (EUA) or conditional marketing authorization (CMA). CMC teams can leverage the experiences to progress accelerated CMC development programs complementary to expedited clinical programs.
Author company affiliation is given at the end of this article. Case study material was developed by authors who were the subject matter experts for the products discussed or by interviewing product subject matter experts. These individuals are acknowledged at the end of the article.
The Case Studies and Their Specific Challenges
A brief summary of each case study is provided here to offer a better understanding of the background and challenges for each project.
Case Study 1: Small Synthetic Molecule
This product was developed in-house and designated for EUA at a very early development stage. Key challenges included rapid development timelines, scale-up requirements, and lack of adequate stability data. Regulatory interactions were helpful and included flexibility to agree on EUA/CMA deliverables and commitments.
| Case Study Number | Feedback |
|---|---|
| 1 (S) | • Strategic, end-to-end launch planning from Day 1 • Commercial sourcing personnel were engaged early, even during the sourcing of clinical materials (for both drug substance (DS) and drug product (DP), raw materials, and manufacturing sites). • In addition, a matrix of multiple commercial DS and DP manufacturing vendors, as well as DP excipient suppliers, was qualified during the clinical stage. |
| 2 (B) | Main challenges: • The Phase 3 clinical trial utilized a vial-based drug presentation, whereas the final commercial formulation was delivered via a prefilled syringe. Bridging between the two presentations was supported through analytical comparability assessments, conducted in alignment with guidance from regulatory authorities in the United States, European Union, and China. • Due to the implementation of the EU MDR, the Notified Body Opinion (NBOp) was unavailable at submission. With agency agreement, the NBOp could be submitted during review. • Use of PACMP for additional DS site flexibility was included with the initial MA. • The initial shelf life at approval was limited due to constrained stability data from primary clinical stability lots used as the basis for the initial expiry date even though a longer shelf life was required to launch and supply product to the market. Additional stability data were submitted during review to extend shelf life at approval, but this also required rapid post approval submission required too support market launch. • MA was filed with no validation or qualification for assembly, packaging, and labeling. • Multiple concurrent submissions led to simultaneous agency requests. Due to accelerated MA reviews (even for agencies not using an expedited procedure), responses to agency questions were due within shortened timelines. |
| 3 (B) | • DS production began at small scale with an initial formulation buffer, later modified for stability and scaled up at selected sites to meet capacity needs. • The initial EUA was filed and included a limited number of DS, DP intermediate, and fill-finish sites, which grew exponentially with rising vaccine demand. Lipid and mRNA supply, along with analytical testing capacity, scaled up in parallel. • Cross-functional teams with experienced personnel were dedicated to enable fast decision-making. Obtaining agency buy-in was key for rapid success. EMA weekly conversations occurred. The FDA provided mainly written feedback within days with telephone conversations at their request. |
| 4 (S) | To meet the challenging timelines set by the clinical program, innovative CMC approaches were developed and agreed upon at meetings with the US FDA and EMA. A lower-strength tablet below the required dose was used during pivotal studies and launch. Though requiring multiple tablets and increasing the risk of dosing errors, the benefit–risk profile was favorable. The final clinical dose was confirmed post approval, and a higher-strength, bioequivalent dosage form was subsequently developed. Additional key challenges covered in other sections of this article include: • Accelerated tech transfer and scale-up at commercial manufacturing sites • Stability data were required to support global shelf and retest periods across all manufacturing sites and DP formats • Process validation strategies to enable compressed timelines • Rapid onboarding of a new DS manufacturing site • Innovative solutions were adopted and accepted by regulators based on a strong benefit–risk profile |
| 5 (B) | To accelerate scale-up using emerging technology, multiple parallel strategies were employed: • Long-lead-time, high-cost equipment was procured to mitigate potential risk of failure of alternative short-lead-time, off-the-shelf equipment. • Development and scale-up studies led to the decision for a scale-out approach for flexible supply. The unknown final dose through development led to significant overage, which was more easily mitigated with a scale-out approach because it was considered easier to shut down a line than to reduce output. • As the process was scaled up, each scale was fully qualified, as it was unclear which scale, or scales, would be employed for commercial production. |
| 6 (B) | A high-yield DS platform enabled sufficient output from a limited number of sites, while multiple external DP sites (primarily CMOs) supported production. |
| 7 (S) | The product, designated as both breakthrough and orphan in the US, was acquired from another sponsor. A contract research organization (CRO) developed the DS and DP processes. To support an accelerated launch, preapproval meetings with the US FDA led to several agreements and novel accelerated launch strategies: • The clinical DS manufacturing site was used for launch, with a commercial site added post approval. • Accelerated US FDA review required novel process validation approaches for an early US launch. DS was initially validated at the clinical site, with those batches used for DP validation and launch. Later, DS was validated at the commercial site. • DP lots without identification markings were initially launched in the US, then replaced within a month of approval by lots featuring the commercial image. |
Case Study 2: Large Biologic Molecule
Developed from in-house research, this product received breakthrough and PRIME designations prior to Phase 3 start. Challenges included bridging from the Phase 3 trial presentation to the presentation included in the MA, new EU Medical Device Regulations (MDR), and limited shelf life at approval. Regulatory interactions were critical for addressing these challenges.
Case Study 3: Large Biologic Molecule
This vaccine was co-developed through a partnership, leveraging prior knowledge and manufacturing experience. Key challenges included identifying an optimal vaccine candidate, managing formulation changes, sourcing raw materials, and ensuring quality control. Effective proactive dialogue with the US (FDA), European Medicines Agency (EMA), and other regulatory authorities was crucial.
Case Study 4: Small Synthetic Molecule
Developed in-house, this product received Orphan Drug Designation and Fast Track Designation during development. The main CMC challenges included process validation, an adequate stability data package, and introduction of manufacturing sites. Innovative CMC strategies were discussed at agency presubmission meetings.
Case Study 5: Large Biologic Molecule
Developed in-house, this product received EUA approval after Phase 3 met the primary efficacy endpoint. Regulatory interactions included a visit from the US FDA prior to the EUA.
Case Study 6: Large Biologic Molecule
Developed from in-house research, this product received EUA approval. Challenges included selection of final drug product (DP) presentation, operational issues, and significant acceleration of technical transfer and manufacturing activities. Regular communication with the US FDA and EMA was conducted to ensure progression of key milestones.
Case Study 7: Small Synthetic Molecule
This product was in-licensed from another company but required extensive additional development. The main CMC challenges included updating CMC aspects of drug development, adding a new drug substance (DS) manufacturing site, and using novel validation approaches. Several face-to-face meetings were held with the US FDA to ensure early commercial approval and launch.
| Case Study | Feedback |
|---|---|
| 1 (S) | No comment given for this learning point. |
| 2 (B) | Leveraged prior knowledge, platform data, and platform formulation—along with robust platform analytical methods—more than in a traditional development program. |
| 3 (B) | Platform technologies were initially unavailable, requiring alternative strategies to accelerate development. Risk-based assessments using prior knowledge helped narrow the scope of process-related impurity characterization and validation. As manufacturing knowledge grew, a platform approach was established post-approval. |
| 4 (S) | Due to accelerated timelines, compared to a standard product development program, the product-specific process characterization data were limited. Therefore, there was greater use of prior knowledge to streamline the additional process characterization work needed. |
| 5 (B) | Platform process knowledge was well developed which supported: • The majority of the methods for analytical comparability were in place, based on the existing platform. • No formal product-specific failure modes effect analyses (FMEA) were used, but FMEA from the platform was used; quality by design (QbD) activities were already understood. • Preidentified critical process parameters (CPPs), in-process controls, and their ranges did not require tightening to the available product data. • By the final scale, full QbD data was established to confirm CPPs. |
| 6 (B) | DS and DP platform processes were used, with supporting data from other products produced on the same platform, leading to analytics and generally robust platform assays. |
| 7 (S) | Platform technology was not used, though standard manufacturing equipment and processes, formulation and analytical methods were used. When the product was brought in from the original sponsor, the quality aspects were not adequately advanced. By using standard processes and methods, prior knowledge within the company was used to bring the product quickly to the required standard. |
Case Study Feedback: Key Learnings
Based on preliminary clinical evidence, drug development programs can be granted a designated accelerated development status at points in the program that differ significantly in terms of source and amount of CMC information, materials, and data that would be available. Despite the variability among accelerated CMC development programs, an extensive review of the seven case studies by the ISPE members has identified some common themes and relatively new beneficial approaches.
These approaches include:
- Project execution approaches that lower risk to approval, including use of expeditious launch strategies, to provide uninterrupted supply to patients
- Greater leveraging of prior scientific knowledge, often labeled platform knowledge, leading to optimized development studies and accelerated development pathways
- Use of models to inform control of the manufacturing process and quality of the product
- Alternative accelerated process validation strategies
- Innovative approaches and strategies in analytical methods and specifications, shelf life, stability, and packaging
- Increased use of postapproval change management protocols (PACMPs) or comparability protocols (CPs) beyond biological product comparability studies, e.g., for site changes for small synthetic molecules
- More regulatory post approval commitments for data than are normally included in filings by the time of authorization
- Organizational ways of working differently
| Case Study | Feedback |
|---|---|
| 1 (S) | This relied on process and equipment models much more heavily than with previous projects; did modeling and went straight to manufacturing (with little to no experimental confirmation or validation of models): • Powder mixing models • Equipment modeling: tableting and flow processes modeled • Relative bioavailability (rBA) studies • Biopharmaceutic modeling indicated “not high” risk, which provided some assurance if late changes were needed, and provided more potential flexibility for changes, e.g., site transfers. However, in continued efforts to minimize risk, because the commercial tablet was rapidly developed in just six weeks, the actual Phase 3 clinical supplies were manufactured at commercial scale at the launch site using DS made at one of the initial supply vendors using the commercial DS isolation process. Using these supplies directly in Phase 3 removed the bioequivalence (BE) risk that would be present if formulation and/or supply changes were introduced later in the development program. Furthermore, multiple launch sites for both DS and DP were justified with crossover in vitro dissolution comparisons to verify comparability in final product without performing studies. Equipment modeling – tableting and flow processes modeled. • Relative bioavailability (rBA ) studies. More detailed discussion of the use of models in this project is given in Appendix 1, which is available with the online version of this article |
| 2 (B) | Applicant relied on extensive prior knowledge of scaled-down models for process development. |
| 3 (B) | • CFD modeling was used to support mixing characterization, scale-up, and tech transfer. It helped determine agitation rates at both small and manufacturing scales, enabling rapid scale-up across sites and equipment with varying geometries. This approach eliminated the need for mixing studies at commercial scale confirmation. A scale-out, as opposed to a scale-up, approach was used to accelerate product development. Adding more mixing vessels instead of switching to larger vessels reduced the requirement for additional development work. • No modeling was used for stability to establish shelf life, as feedback from health authorities was that the real-time stability data on primary batches/lots is required. |
| 4 (S) | The DS retest period and the DP shelf life were both supported by ASAP modeling studies. An ASAP study was also supportive of changing from uncoated tablets to coated tablets during development. See the packaging section for use of Moisture Vapor Transmission Rate (MVTR) modeling. |
| 5 (B) | Scale-down model qualified |
| 6 (B) | 1. DP process modeling defined process operating ranges for critical parameters thawing, mixing, DP freezing, etc., and their impact on CQAs. Results were confirmed by production-scale verification studies (process performance qualification [PPQ] lots) during technical transfer of the process to manufacturing sites. This approach provided acceleration and reduced resources for the technical transfer to new manufacturing sites. 2. Modeling was used to confirm shelf life claims. See the stability learning points. |
| 7 (S) | A physiologically based pharmacokinetic (PBPK) model was used to set dissolution acceptance criteria. The model itself was determined not to be adequate by the US FDA at the time of NDA approval, though the acceptance criteria was considered acceptable. |
In the following sections, each key learning is summarized and followed by a table derived from interviews with subject matter experts for each case study. The tables include a column indicating whether the project involved small synthetic molecule (S) or large biologic molecule (B) ,as defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q6A7 and Q6B.8
Project Execution that Lowers Risk to Sustained Supply
In at least two case studies, an interim formulation and manufacturing scale (clinical scale and site of manufacture) were initially progressed and approved, with commitment made to improve the formulation or modify the scale and/or site of manufacture following approval. This approach exemplifies early decision-making, with revisions ideally planned for the post approval. A PACMP or CP in the original MA submission is an alternative to a commitment and may reduce the timeframe for the post approval change. For this article, MA may be interpreted as a New Drug Application (NDA), Biologics License Application (BLA), or Marketing Authorization Application (MAA) as appropriate.
Deferral of formulation (strength) changes may be needed to allow optimization of the size of the final strength dosage unit for patient acceptability and compliance. Formulation may also be changed to improve product stability or optimize manufacture. Deferred manufacturing scale changes may need to be implemented rapidly after initial MA approval and may be facilitated by the CP or PACMP approach. Use of CPs or PACMPs provided predictability and efficiency in prosecuting CMC changes as given in ICH Q12 compared with the historical approach.9
For each case of interim formulation and scale, the CMC content of the MA submission is not reduced, and the initial authorized product is of the expected quality, safety, and efficacy. Additional actions to minimize risk and increase the chances of successful product approval, while meeting the timescale, are described in the following case study feedback table.
| Case Study | Feedback |
|---|---|
| 1 (S) | Extra testing was performed on pivotal clinical lots in lieu of process validation for the CMA/EUA filing. EU and US regulators were notified prior to filing (i.e., informal communication and not a meeting or a formal briefing document). |
| 2 (B) | Some data to complete DP validation and limits for a CPP for device assembly was not available at the time of initial EU filing but was planned to be available at the time of the first regulatory questions. |
| 3 (B) | • Concurrent validation approach using a network strategy: Concurrent validation was exceptional for a new vaccine, but this strategy was accepted because it was a medically necessary drug and it was justified based on the body of development and clinical/GMP data that was available. A network process validation protocol and comparability protocol were used to demonstrate the capability of the DP manufacturing network to consistently and reproducibly manufacture the vaccine. An enabler for this network validation approach was site collaboration and ensuring that the same process with the same CPPs, critical quality attributes (CQAs), and specifications were implemented at each site. • For the EUA, data from three sites―each with one validation lot―was submitted to the US FDA as it became available. For the post-EUA full BLA, a concurrent validation approach to provide the data from the process validation runs was endorsed by the agency. This was referred to as network validation submission. To complete the full validation package and submission, two additional process validation batches at each of the three sites were performed. • Bracketing and matrixing strategies: During the EUA phase, fewer than three DP process validation batches were acceptable when justified by a bracketing or matrixing strategy supported by strong process knowledge and comparability data. These approaches relied on well-documented comparability assessments. These strategies were applied when the process comparability concluded there was similarity in the process and equipment (e.g., filling lines, batch size). Platform manufacturing strategies: The DP manufacturing platform was validated through three process validation runs at each site. A validation risk management exercise was conducted as part of the platform strategy to assess whether post approval changes would impact the validated manufacturing process or fit within the established platform. If the change retained the fit within the established platform, existing process knowledge could be leveraged. To justify the impact on validation, a confirmatory batch—executed at commercial scale under protocol—was used to demonstrate product quality for updated manufacturing processes, such as those for new variants. |
| 4 (S) | • The manufacturing process for the initial commercial tablet was validated using a decoupled process validation approach for the process validation runs. Clinical DS batches, representative of the intended commercial DS, were used for DP process validation runs and commercial DP batches were distributed concurrently with the ongoing DS process validation campaign. • The commercial DS manufacturing process validation protocol was performed in parallel with commercial DP manufacture and distribution, thereby reducing the time required for an end-to-end process validation campaign from commercial DS to commercial DP. • DP manufactured from the DS process validation runs were used for launch. • As is normal for a synthetic chemical entity, the process validation run data were not provided in the MA. • Through agency meetings, prior agreement for the process validation approach was sought from the US FDA and EMA. |
| 5 (B) | Validated initial, intermediate, and final scales: Large amounts of data were obtained in a short period of time: • Internal discussions to identify critical vs. non-critical parameters to establish process parameters. • Erred on the side of caution in designating a process parameter as a CPP. Normally more development would be performed to classify parameter criticality. No attempts were made during agency review to challenge the CPP assignments. • Non-GMP extended characterization assays were used to demonstrate comparability through the development process. • Parallel assay qualifications were conducted during process development. • Because of the COVID-19 pandemic, we knew all batches would be used: three runs on the first manufacturing location/equipment train and one run on subsequent trains. • Decoupled DS and DP process validation. • DS was split into two: a) mRNA and b) lipid nanoparticle. The applicant decided not to push for one DS so as not to delay submission review. • DP process was contracted out. • After process validation, 30 batches of extended characterization were ran. • Submitted PACMP with acceptance criteria with EUA. The process was adjusted within pharmaceutical quality system criteria instead of bundling process changes in a postapproval supplement prior to BLA. • By BLA, had all data to support scale-up and scale-out. • EU production was filed only in EU; US production was filed only in US. |
| 6 (B) | • Process validation of DS and DP was decoupled, with three DP PPQ lots at each site. The PPQ lots employed a common strategy across sites for cumulative hold times, with site-specific approaches to hold times pursued according to the scale at that site. • Process validation included postapproval Stage 3A sampling for additional testing to understand process variability, in addition to routine Stage 3b continued/ongoing process verification. As subsequent DP sites were brought online or validated, PPQ sampling needs were reduced. • For the DP PPQ lots, three batches of release data (CoA), meeting release specifications per site, were agreed upon with the EMA to be submitted in the initial MA, with the stability data from these batches to be submitted post-approval. There was parallel validation of analytical testing at multiple testing labs. |
| 7 (S) | DS and DP process validations were performed in parallel (decoupled). The first set of DP process validation lots were validated using DS clinical batches. A second set of DP process validation lots was validated postapproval when the validated DS batches were available. |
Increased Use of Prior Scientific Knowledge
Although prior knowledge has been used routinely in regulatory submissions for many years, these applications were more restricted in scope—e.g., determination of quality attribute criticality and manufacturing process characterization—compared with the products in the case studies where prior knowledge was used to maximize and accelerate submission readiness of the MA. Extensive use of prior scientific knowledge or platform knowledge was applied in many areas of the accelerated development programs. It is recognized that there is not a common definition of “platform technology” as used by industry and in this article.
Advanced levels of company expertise generated substantial prior knowledge in the manufacture of a given molecule type, which coupled with careful planning led to optimized quality risk management (QRM) exercises. The output from these QRM exercises led to streamlined development, process characterization studies, and validation studies.
Increased Use of Modeling
Modeling was extensively used across a wide variety of applications, including:
- Manufacturing process development
- Equipment comparisons
- Biopharmaceutical comparability
- Effectiveness of packaging materials and packs (discussed in detail in the packaging section)
- Supportive data for shelf life claims
Although not specifically leveraged in the case studies, alternative approaches for determining DP shelf life are considered to be one of the most impactful areas to accelerate product development. In lieu of extensive long-term data, these alternative approaches rely on robust modeling. For small molecules, extrapolation allows some extension beyond long-term data. However, the use of an accelerated stability assessment program (ASAP) approach would provide additional assurance of predicted shelf life while potentially requiring less long-term data.
For large biological molecules, ICH Q5C does not support the use of stability models to set shelf life, and agency expectation remains that shelf life is based on three primary stability batches with long-term data through shelf life.10 Agencies have historically been reluctant to accept alternative, justified approaches. The industry looks forward to the revision of the ICH Q1 Stability guidelines, which are expected to include considerations for stability modeling.11
| Case Study | Feedback |
|---|---|
| 1 (S) | Phase-appropriate method validation was used through development, with methods fully validated for the MA submission. The team transferred Phase 2 methods in parallel with DP manufacturing process transfer as part of the Phase 3 supply manufacture . Dissolution test: • Focused on unique rotamer conversion to justify the required surfactant level; an interim method was authorized, with a commitment to finalize the method – post authorization. • Wider acceptance criteria were agreed upon as part of the EUA due to limited batch history (four batches), then the team developed subsequent variant tablet evaluation in the dissolution method to confirm wider acceptance criteria . Because the DS process was locked into the final step of the process early on, the DS impurity profile did not change much . Also proposed were wider acceptance criteria, with a commitment to tighten them later when more batch history was available . |
| 2 (B) | The use of platform specifications and platform analytical methods, when applicable, resulted in fewer agency questions. |
| 3 (B) | • To accelerate EUA readiness, the clinical laboratory was converted into a commercial lab, minimizing method transfers. This approach was essential to support the speed and agility required by the program, which eliminated most analytical method transfers to the intended long-term commercial laboratories. Orchestration of this strategy required most activities to be performed in parallel. • Activities consisted of sequestering laboratory space, organizing laboratory management and scientists, and locating, relocating, and installing equipment and instrumentation in a common GMP laboratory, all while concurrently gaining analytical expertise as part of product development. Existing laboratory quality systems were scrutinized to ensure current regulatory expectations for commercial operations were met. A well-documented QRM approach was used to conduct assessments, define potential gaps, assess risk, and take remedial actions when needed. • Later, transferring methods to commercial manufacturing sites required rapid coordination among key manufacturing and analytical stakeholders presented additional analytical challenges. They identified analytical methods required for manufacturing technology transfer, initial Process Performance Qualification (PPQ), and subsequent commercial campaigns. Demonstration of commercial laboratory testing capabilities for these analytical methods was prioritized for compendial and non-compendial analytical methods. • Method transfers focused on key in-process and stability-sensitive tests required for manufacturing monitoring and/or control. Microbiological testing was verified concurrently with the first commercial manufacturing campaigns. Analytical method transfers for all quality attributes were then transferred to the long-term commercial testing laboratories. |
| 4 (S) | No comment given for this learning point. |
| 5 (B) | • Existing platform provided knowledge and the primary basis for initial specifications, e.g., purity impact on immunogenicity. Acceptance criteria were tightened based on process performance as manufacturing experience was gained. |
| 6 (B) | Specification setting was based on platform knowledge. Platform-based assays were generally considered robust. Non-compendial methods were validated for product-specific data. |
| 7 (S) | No comment given for this learning point. |
Use of Accelerated Process Validation Strategies
Many different accelerated validation strategies were reported, which were dependent on the data available, development approach taken, and experience with full-scale manufacturing prior to validation. Some common considerations were the use of:
- Concurrent process validation
- Decoupled process validation
- Process and product characterization
- Platform strategies
In all cases where process validation was not provided to the agencies, commitments were made to complete process validation. The design and acceptance of a process validation approach highly depends on the benefit–risk ratio for the product and its therapeutic indication. These dependencies differed among the case studies, leading to various process validation approaches. For example, concurrent process validation is commonly used for small synthetic chemical entities but is rarely accepted for large biologicals. Therefore, the use of a manufacturing network approach applied to a biological vaccine product may be of particular interest in supporting concurrent process validation according to medical need.
The use of decoupled process validation is increasing across therapeutic modalities. This approach compresses time by validating the DP manufacturing process using clinical process and site DS, provided it is representative of the intended commercial DS. However, launch may not be supported using this DP material. When conventional process validation is applied, it may be possible to defer submission of less critical testing data, including maximum cumulative hold time, until review or potentially postapproval.
| Case Study | Feedback |
|---|---|
| 1 (S) | Stability studies were performed on every lot manufactured: • At the time of filing, there was one early prototype, one Phase 1 tablet, one prototype from Phase 3, four Phase 3 batches (three of the four were used as primary stability lots according to ICH protocol). Most of these batches only had three months of stability, with data provided to the agency as soon as it became available during review. • Only trend was for temperature/moisture. • Packaged in foil blisters to be conservative. |
| 2 (B) | Representative pilot-scale lots were used as stability batches, and shelf life was based on the stability batches. The team requested a longer shelf life in the initial filings than initial data allowed, with the caveat to provide data during review at the time of agency questions. |
| 3 (B) | • For initial submission, there was limited prior knowledge to leverage. Development stability data was used as supportive data, but most agencies required real-time stability data on primary lots/batches. Agencies allowed rolling submissions of data as it was being generated. • After initial approval, additional post approval change submissions used science- and risk-based approaches to develop strategies for confirmatory stability studies to support post approval changes, which enabled more timely filings, approval, and implementation of the change. The scope and design of such stability studies are informed by the knowledge and experience of the DS and DP acquired since authorization. |
| 4 (S) | Overall, the DS and DP showed little change or variability in the stability-indicating quality attributes over time when stored at the recommended or accelerated conditions. These conclusions supported the selection of primary stability lots and an extrapolation approach for DS retest period and DP shelf life. Agency meetings were held to gain agreement on the stability strategy. • DS and DP from early development and pivotal clinical stability lots were demonstrated to be representative of the DS and DP. Therefore, the three primary stability lots were from different earlier manufacturing processes, at pilot scale, and were sufficiently justified as representative of the final production-scale processes. • The DS primary batches’ stability data supported a 24-month retest period for the commercial product. This was by extrapolation from 18 months, 12 months, and 6 months of stability data available from the three primary lots, at submission, supported by additional stability data (up to 3 months) provided during review. • EMA submission was later than for the US FDA, with 24 months and 12 months of stability data for the primary batches. Additional supporting batches provided data through to the retest period. Note that, at the time, providing stability data during review for the US FDA was less common than it is today. • Stability data was provided from two DS manufacturing sites, though it was accepted that the primary stability data could be from one site. The retest period could be transferred across the two manufacturing sites since the DS from both sites were representative of each other. • Similarly, DP stability data supported a 24-month shelf life by extrapolation from three DP pilot scale, primary lots stability data (i.e., the US FDA, initial submission, tablets in bottles), at 12 months and 9 months at submission. The EMA submission included both bottles and blister packs with 12-month stability data. Shelf life was extrapolated across packaging. Due to submission timing compared to the US FDA, the EMA initial submission had up to six months of additional stability data, with up to a further 6 months provided during review. |
| 5 (B) | • There was only very early stability data with small pilot scale (< 1/10 commercial batch size); however, the US FDA allowed use of that scale. • The project allowed a three-month shelf life based on the small pilot-scale stability data with only one month of stability data on the production scale. This was a sufficient initial shelf life to support initial launch under EUA. |
| 6 (B) | The stability/shelf-life strategy was agreed upon through scientific feedback from the EMA. Extensive modeling was used to support initial shelf-life claims in the initial MA submission, based on platform data from other similar products. Regression analysis for the best-fit slopes was used to extrapolate stability data to the claimed shelf life. Release limits were adjusted to support extended shelf life at 2–8°C. Long-term stability data to support the shelf life and confirm the model using the three PPQ lots as the primary stability batches were provided post approval. |
| 7 (S) | No comment given for this learning point. |
...concurrent process validation is commonly used for small synthetic chemical entities but is rarely accepted for large biologicals. Therefore, the use of a manufacturing network approach applied to a biological vaccine product may be of particular interest in supporting concurrent process validation according to medical need.
Analytical Methods and Specifications
Leveraging platform knowledge was commonly used to justify specifications. A commitment to tighten specification ranges after manufacturing experience was gained was also made in several cases. The use of platform assays reduced the risk of analytical method delays. In one case, the conversion of a clinical facility into a GMP testing site for commercial manufacture avoided the time and resources required to transfer analytical methods.
Stability
Many case studies used development stability study data to support shelf lives. Modeling was also used in some cases to support shelf life predictions and moisture and oxygen transmission through packs. Extrapolation of stability data to extend shelf life beyond the available long-term stability data at the recommended storage condition was generally not accepted for large biologicals, due to the perceived level of inherent instability for biological products and the strictures of ICH Q5C (see the Increased Use of Modeling section). From the described case studies, there was one interesting exception for an agency, in which regression analysis of the product stability data to shelf life was accepted when supported by prior knowledge stability data from similar molecules through to the product’s approved shelf life.
Generally, additional stability data through to shelf life could be provided during agency review, or, in the case of the exception, provided post approval. At best, additional stability data through to shelf life could be provided during agency review. Even for small synthetic chemical products, extrapolation was often expected to be supported by long-term stability data to shelf life that could be provided during agency review.
| Case Study | Feedback |
|---|---|
| 1 (S) | Only foil blisters and initially only US/EU packages/inserts (more local details were provided in relevant sections of EUA). |
| 2 (B) | Packaging materials did not create any regulatory issues. |
| 3 (B) | No comment given for this learning point. |
| 4 (S) | • Open-dish data supported changing from uncoated to coated tablets during development. • Uncoated tablet stability data was used to support the coated tablet stability package. • Due to limited product knowledge and the impact of moisture, clinical studies used products with fully protective packaging, including a desiccant. When moving from clinical to commercial, the desiccant was removed to streamline DP manufacture, as supported by the open-dish stability data. The MVTR of the primary container (bottle and blister) was modeled and correlated to DP data. |
| 5 (B) | No comment given for this learning point. |
| 6 (B) | Started with two packaging configurations, one for the US and one for the EU. Initially all text was only English, with a simplified artwork strategy; however, country-specific requirements were added over time, post approval (e.g., leaflets, stickers). |
| 7 (S) | No comment given for this learning point. |
| Case Study | Feedback |
|---|---|
| 1 (S) | No comment given for this learning point. |
| 2 (B) | Platform technologies were used for this product. |
| 3 (B) | No comment given for this learning point. |
| 4 (S) | No comment given for this learning point. |
| 5 (B) | Must be disposable • Kit: Equipment list defined. • No variability in manufacturer. • All items in the manufacturing suite were predefined—worked well for technical transfer. • One user requirement specification, equipment qualification accelerated. |
| 6 (B) | DS and DP processes were fully disposable. This brought significant benefits to production but also risk to: • Stock/supply of disposables became the limiting factor. • Supply chain of disposables can be long, materials were shipped from location to location to add components, perform tests, gamma irradiate, etc. • Transport was difficult, and, in some cases, countries blocked the export of materials. |
| 7 (S) | No comment given for this learning point. |
| Case Study | Feedback |
|---|---|
| 1 (S) | Synthetic route: Commitment to put final synthetic route/process on primary stability and perform process validation (some small changes were still occurring to the synthetic route when the initial MA filing was submitted); however, no changes to final step or specifications. • DP manufacturing process: In the initial EUA submission, agencies agreed to remove a redundant blend/mill step that had been used for clinical supplies and primary stability batches. The more streamlined commercial DP manufacturing process was supported with additional in-process control testing on stratified samples. • After the EUA phase, a formal process validation was conducted in alignment with the process filed in the final MA submission. • For both DS and DP, final processes were fixed, and validations were performed prior to filing the full/final MA. |
| 2 (B) | DS site addition PACMP filed with the initial MA. Resulted in successful shortened approval time to register the new site, once data was available postapproval in the EU and Great Britain. |
| 3 (B) | No comment given for this learning point. |
| 4 (S) | To ensure sustained supply: • The initial MA submission included information to support the introduction of an additional DS commercial manufacturing site, by including PACMP or CP in the respective regional dossiers, thereby reducing the supplement/ variation category to Type IB/CBE-30. • The PACMP/CP was implemented after MA approval. |
| 5 (B) | No comment given for this learning point. |
| 6 (B) | No comment given for this learning point. |
| 7 (S) | Launched the product using a clinical DS manufacturing site. The DP manufacturing site was also not adequate for the global supply chain. Immediately after the initial NDA approval, by the US FDA, the company added additional DS site without use of a CP and DP manufacturing site using a CP. |
| Case Study | Feedback |
|---|---|
| 1 (S) | Team was twice the normal size, fully focused on this project (circled resources), and could get more resources if needed. • This comes with a cost to other projects (because they took a back seat), which can create a severe impact on other projects and the portfolio. • Governance only scrutinized costs greater than US $1 million, which allowed much more flexibility (i.e., no haggling) on lower costs. • The team had first call on all governance bodies; the team made decisions and often only informed decision makers (could have meetings within 24 hours to get decisions when needed). • Digital technology and automation of data collection to get submission ready was standard practice for this project. • The team wrote submission-ready reports. • Entire EUA submission prepared in 6 weeks. Specifications set only on batch data, and limited stability made the submission one-third of the usual size. • Dedicated team authored the regulatory submissions. |
| 2 (B) | Operated with standard internal development processes and resources except for the DP validation and labeling and packaging qualifications, which were run at a significantly shortened time from validation completion until submission filing. There were several significant post approval burdens due to the shortened timing for the DP and labeling/packaging validations. |
| 3 (B) | No comment given for this learning point. |
| 4 (S) | Collaborative workspace and dedicated team members • Agile direct access to senior leadership for quick decisions. • The team used project management tools. • Rolling submission under the Real-Time Oncology Review (RTOR) program in the US. |
| 5 (B) | Company considered that its development processes for related products constituted a platform. Consequentially, the new product development program was heavy on data available early. Company hired experts with commercial experience. |
| 6 (B) | For operations, a dedicated organization was set up to monitor/control production and inventory, with direct involvement of senior leadership. This included a relatively small team with high frequency interaction and standardized reporting structures. Filing was organized by a separate team that had a lot of platform knowledge. |
| 7 (S) | No comment given for this learning point. |
Packaging
There was some success in using a limited range of packs and presentations (i.e., languages: English) at the time of launch after accelerated development and approval. Movement to local language was required after approval. A proposal to use a QR code for a package leaflet was made but not accepted. It seems this may be a possibility in some regions for some products. Initial use of more protective packaging was a “normal” consideration. Changes in packaging during product development may be supported by open-dish studies and MVTR modeling.
Technologies Applied to Enable Acceleration
The use of disposable, single-use equipment was a key part of the accelerated development program in two case studies; however, this came with significant risks relating to the supply chain for disposable components. The use of portable, modular facilities designed to use the same equipment, material flows, etc. is proving particularly valuable for relatively small volume manufacture of products with short shelf lives and/or requiring special transportation.
Flexibilities of Using PACMPs, CPs and Regulatory Commitments
Although detail is not given in this article, all projects in this review required large amounts of post approval activity, which required significant industry and regulatory resources. In one case, thousands of commitments in response to multiple agencies were made, with many of the commitments being different between regions.
Organizational Ways of Working Differently
Some common themes that were essential or extremely beneficial were the use of a) dedicated teams with direct access to leadership that were empowered to make decisions; b) specialist, dedicated, and experienced teams for constructing and filing sub-missions; and c) end-to-end digitizing of data from laboratory to submission.
Conclusion
The experiences drawn from seven accelerated development programs demonstrate significant acceleration is achievable when manufacturers implement multiple innovative approaches and actions to meet CMC requirements. Although the details of the actions taken by each case study manufacturer to accelerate development are clearly unique, there were common strategies, including early engagement with the agencies to obtain agreements for the MA submission as well as a post-approval change management plan. These engagements improve the likelihood and speed of approval of innovative approaches for drug development studies as well as the content of MA submissions. These themes included leveraging prior scientific knowledge (“platform knowledge”) to inform risk management, design, and operations—streamlining process and analytical development and validation; applying innovative strategies for formulation, scale, and site selection; using modeling to supplement limited data; adopting alternative process validation approaches; and implementing an organizational structure that enabled rapid decision-making and execution.
Also, manufacturers achieved acceleration with a multitude of other resourceful strategies related to analytical methods, specifications, stability, packaging, and leveraging PACMPs. Companies reported that all normally expected CMC information was provided to the agencies either in the initial filing or post approval. A combination of provision of this information to agencies and confidence of industry and regulators in the science- and risk-based approach assured patient safety and efficacy at initial access to patients (when using EUAs) or approvals, and subsequently.
Agencies should consider evaluating the information provided for EUAs in comparison to MAs, ensuring that the data required for full approval is optimized. There can be no prescriptive template for the CMC activities of product development within an accelerated program such as breakthrough therapy (US) or PRIME (EU). However, the successful strategies and elements presented herein provide insight and potential opportunity for manufacturers of products granted an accelerated designation.
Acknowledgments
The authors would sincerely like to thank the following contributors to the article: Monica Batra, MS, RAC, Amgen; Paula Ruch, BA, Amgen; Nina Corin, PhD, AstraZeneca; Patrick Daugherity, MS, Pfizer Inc.; Pankaj Doshi, PhD, Pfizer Inc.; John Smart, PhD, AstraZeneca; Adrienne Stafford, MS, Pfizer Inc.; Bob Walters, PhD, Pfizer Inc.; Brenda Carrillo Conde, PhD, Pfizer Inc.; Maria Cabrera-Diaz, BSc, Pfizer Inc.; Daniel Hemminghaus, BSc, Pfizer Inc.; Amy St. Charles, MSc, Pfizer Inc.
