Process validation is a key part of the development and manufacture of all approved drug products, but its completion can be a daunting task. At a two-day CASSS CMC Strategy Forum held in July 2016 in Gaithersburg, MD, speakers and attendees addressed the many technical, practical, and regulatory facets of drug product process validation and comparability. In part 1 of this report, we summarize the key discussion points of the first day, which focused on analytics and comparability.

Session One: Analytical Tools for Drug Products
Container–Closure Integrity Testing and Control: Michael Koby (Pfizer) started his presentation with a summary of the BioPhorum Operations Group (BPOG) publication on container–closure integrity (CCI) control and its comparison with integrity testing during routine manufacturing (1). The white paper describes the evolution of the CCI testing (CCIT) landscape, including a push toward 100% in-line CCIT during manufacturing.

Koby mentioned that the latest revision of USP Chapter <1207> suggests that 100% in-line CCIT currently is integrated throughout the biopharmaceutical industry (2), but that is not the case yet. The scope of BPOG’s paper is manufacturing drug products in sterile containers, focusing on an integrated, holistic CCI control. A number of items feed into that, including the CCI test method itself, CCI for commercial stability, change control processes, primary package design, product manufacturing processes, and the manufacturing process of container–closure materials.

The core of Koby’s presentation focused on CCI test methods. Method selection is based on considering the type of container–closure system (e.g., vial, cartridge, or syringe), the drug product, and the leak concern (entry of microorganisms, escape of product dosage, or entry of external gas/liquid/solid matter). Koby discussed different CCI test methods, including dye ingress or leak test, vacuum or pressure decay, headspace analysis, and high-voltage leak detection. No single method is suitable for all container–closure systems, and only the latter two are compatible with 100% on-line testing.

Part of CCI control is ensuring that incoming components meet purchase specifications and that in-process controls are established (e.g., inspection of residual seal force). After filling, a final product undergoes visual inspection (in-line or off-line) to provide assurance that integrity-related product attributes (e.g., stopper position and seal quality) meet expectations and are free of defects.

Another aspect of CCI control is establishing packaging-component specifications and assessing robustness of an assembled package. A significant part of every holistic approach is change management. CCI is controlled through assessing the impact of changes on each function in a holistic approach.

Stability and ensuring integrity during a stability program make up the final branch of a holistic system. Regulatory guidance recommends CCIT for stability (3) in lieu of sterility testing because it is more reliable. Koby mentioned that an integrated holistic system is not a set-it-and-forget-it approach, but instead must be a dynamic system with controls that constantly reassess and reevaluate every aspect.

Koby concluded his presentation by highlighting the benefits and challenges of implementing 100% CCIT. The obvious challenge is that methods must not be destructive and must be compatible with older manufacturing lines. An important benefit is assurance of seal integrity and real-time feedback to help with investigations. Overall, sponsors must select, justify, and validate test methods to be used for their container–closure systems.

Impact of Excipients on Drug Product Analytical Methods: Ashutosh Rao (US Food and Drug Administration Center for Drug Evaluation and Research, FDA CDER) provided a comprehensive overview of the issues associated with analytical testing in the presence of typical drug product excipients. He emphasized the integral role that analytical methods in control strategies for product quality play when potential excipient influence on analytical results must be taken into account.

After describing the lifecycle of analytical methods, Rao highlighted the excipients most frequently used with biotechnology products and their specific properties. As of July 2016, the Office of Biotechnology Products had 143 licensed or approved protein therapeutic products with more than 185 unique formulations or presentations. Sponsors must select and justify excipients to ensure the high quality and stability of their drug products. Although excipients provide benefits to biopharmaceuticals, they also might adversely influence drug product quality. Rao provided a few examples such as antimicrobial preservatives that can induce protein aggregation.

Among all excipients encountered in an FDA-licensed drug product, human serum albumin (HSA) is of particular interest. HSA is a naturally sourced stabilizer, but it interferes with a number of analytical and immunologic assays. Assays then must be modified to prevent or minimize such interferences. Certain other excipients such as polysorbates and polyethylene glycol (PEG) have UV absorbance and broad chromatographic profiles that can interfere with analytical methods. Thus, analytical testing should be improved to include monitoring and controlling for interference from excipients and impurities. The FDA encourages sponsors to engage in early communications regarding specific concerns and challenges with unique or novel excipients, their interactions with products, and potential interference with drug product testing.

Multiattribute Method (MAM): Tamer Eris (Amgen) presented an application of a MAM for quality control (QC) release and stability testing of protein therapeutics. The MAM is based on a mass spectrometry (MS) peptide-mapping method that provides direct and simultaneous monitoring of relevant product-quality attributes such as oxidation, deamidation, polypeptide-chain clipping, and posttranslational modifications. A MAM can become a platform-based method that follows quality by design (QbD) principles. It can identify and select critical quality attributes (CQAs) during process development that can later be implemented in QC for release and stability testing. MAM has potential to replace some indirect conventional assays, driving down the cost of QC testing. Examples of such assays include those for purity using capillary electrophoresis–sodium dodecyl sulfate (CE-SDS), charge variants using cation-exchange high-performance liquid chromatography (HPLC), glycan mapping, protein identity using immunoassays, and specific process impurities such as leached protein A enzyme-linked immunosorbent assay (ELISA).

This MAM can detect new species that are not in the reference standard. That is one justification for its use in QC areas. Software applications examine all portions of a mass spectrum from a tryptic digest sample and compare each mass spectrum portion with the equivalent portion of the reference standard spectrum.

Finally, Eris explained how to develop, qualify, and validate MS-based MAMs. Overall, by virtue of isotopic mass fingerprinting and the ability to quantify a specific attribute, such MAMs provide a scientifically superior approach than do non-attribute-specific assays. It can be applied across modalities and provides flexibility as knowledge increases during clinical development.

Drug Product Comparability: Jamie Moore (Genentech) spoke about the use of process and product knowledge for a successful comparability exercise. She quoted the three basic questions that Genentech asks about assays in a comparability exercise: What do we need to measure? Do we have reliable methods? What’s an acceptable result?

Moore provided examples of drug product comparability studies to illustrate approaches to using process and product knowledge. In one example, a process change requiring extended mixing for homogenization of a protease product was evaluated for clipping, particulates, and product loss. A small increase in subvisible particles was observed, but using different filters downstream provided assurance that high product quality was maintained.

For selection of comparability acceptance criteria, Moore referred to the 95/99 tolerance interval (TI) of the historical lot data, which sometimes can be tighter than a specification range. A 95/99 TI is an acceptance range in which 99% of the batch data are within this range with 95% confidence (4). She mentioned that in addition to ensuring that specifications and the 95/99 TI criteria are met, sponsors should scrutinize trends in their results to determine whether an investigation should follow. For one product, data for particles sized 10 μm and 25 μm were reliable and tightly within the 95/99 TI criteria, but data for particles sized 2 μm and 5 μm were highly variable. For comparability assessment of the latter two sizes, a “report result” was used, with the caveat that the drug product was to be used with an intravenous bag with an in-line filter.

Moore presented an example of how extended characterization studies were conducted beyond release testing. The objective was to support a process change from a lyophilizer sterilization method to one that used vaporized hydrogen peroxide. Spike studies of hydrogen peroxide into a drug product were conducted for up to 100 ng/mL, and product stability was assessed. Results showed that peroxide levels reached below limit of detection (LoD) by six months, and no increase in product oxidation occurred for up to 30 months.

Moore then discussed stress studies as a sensitive comparability tool. Typically, degradation in short-term and high-temperature stress studies (e.g., one week to two months at 15–20 °C below melting temperature, Tm) are evaluated at a few time points. She emphasized the importance of side-by-side testing, mentioning a monoclonal antibody (MAb) that was sensitive to 40 °C (instead of 40.5 °C). The mode of degradation is assessed qualitatively by comparing chromatographic and electrophoretic profiles at each time point, looking for new peaks, and confirming similar peak shapes and heights. Degradation rates can be compared graphically for all attributes. Finally, a statistical assessment is performed on the degradation rates for select assays, looking at homogeneity of slopes and ratio of rates.

Panel Discussion on Analytical Tools for Drug Products
After those presentations, the speakers and cochairs participated in a panel discussion. They were joined by Ewa Marszal from FDA’s Center for Biologics Evaluation and Research (CBER) and Robert Simler from Biogen.

Excipient Control and Impact on Drug Product: Polysorbate degradation resulting in subvisible particles is an example of how excipients can compromise drug product quality. Controlling polysorbates can include putting a limit on released fatty acids or removing the host-cell phospholipases that cause polysorbate breakdown.

For excipients with a functional claim (e.g., antioxidants and polysorbates), regulatory agencies expect sponsors to monitor excipient stability and confirm that those excipients still can perform their functions throughout a product’s shelf life. Health authorities also expect that novel excipients are fully characterized. They have observed cases of common excipients that take on novel characteristics when used in certain combinations.

An example of interference with drug product analytical methods is the presence of leachables from sterilized syringes used for drug administration. Such particles can interfere with a reversed-phase HPLC purity assay. FDA and industry scientists also have observed differences in heterogeneity and purity of complex excipients (e.g., polysorbate 80 or PEG) from different suppliers. Different impurity levels have been detected for a biological excipient (albumin) from different expression systems. Thus, an analytical strategy should take into consideration that such excipients can create variable interference with drug product analytical methods.

CCI Test Methods and Control: Most common CCIT methods have technical limitations but continue to be used in the biopharmaceutical industry. FDA regulators understand such limitations and encourage sponsors to use orthogonal methods when possible.

The industry is trending toward preferring quantitative methods (e.g., UV signals) over visual assessment for dye-ingress methods, but that development is slow in emerging. Attendees were reminded that at the 2016 CASSS Well Characterized Biotechnology Pharmaceutical (WCBP) conference, Patricia Hughes (FDA) commented that a dye-ingress test is acceptable if a validation study and QC system suitability of positive control use particles of appropriate small size. For dye-ingress testing, a 10–15-µm leak size is appropriate as a positive control. A 20-µm leak size might be acceptable if justified for a given container–closure and drug product. For lyophilized products sealed under vacuum, one company uses laser spectroscopy for 100% in-line inspection. That company worked with a supplier to set pass–fail criteria using leak sizes of 5–10 μm.
For prefilled syringes, the FDA is concerned that a plunger might move into the nonsterile portion of a barrel because of pressure changes during shipping. There are no special considerations for CCI testing of frozen drug product vials beyond normal considerations for CCIT. The FDA’s major concern is safety of extended-use (multiuse) container–closure systems when microbial contamination risk is high for certain types of product.

Subvisible Particle (SVP) Quantitation and Control: For small-molecule therapies, the concern with SVPs >10 μm and >25 μm is a physiological one (e.g., clogging capillaries or renal tubules). The presence of such SVPs in biopharmaceuticals also is a concern, as is the presence of proteinaceous (endogenous) high–molecular-weight (HMW) species that appear after production or that form over time and span a wide range of particle sizes (4). Some biopharmaceutical companies have product-specific limits on SVPs sizes 10 μm and 25 μm that are tighter than compendial limits for products with a low number of SVPs (e.g., tens to hundreds of particles per container). Requirements for generating increased characterization data have pushed some companies to decrease SVPs as part of drug product formulation development.

No single test method can cover the full size range of SVPs. Currently, a measurement gap exists between 100 nm and 2 μm. The FDA has encouraged sponsors to characterize particles between 0.1 μm and 2 μm as more methods become available (5). Light obscuration is the primary method for SVP testing per USP <787> and USP <788>. Flow imaging is used for particles 2 μm.

In one biosimilar comparability study, flow imaging was used when light-obscuration results were out of trend. Other comparability studies use flow imaging when there are changes to a container–closure system (e.g., vial to prefilled syringe). If the number of particles at USP sizes is low, then the FDA expects sponsors to use a more sensitive method for assessing SVP comparability, recognizing that establishing acceptable comparative ranges for SVPs can be difficult. Those data must be assessed for potential product safety issues. If safety risks arise, the FDA will expect more data on the nature of SVPs because different products can form different types of SVPs that have different biological effects (e.g., cytokine release). To the question of what techniques are being used for submicron particle characterization, reference was made to an industry consortium paper on that subject (6). Aggregates have been characterized by MS, including hydrogen–deuterium exchange MS to assess higher-order structures.

Although in-line filters can remove SVPs, sometimes particles reform after filtration. Sponsors should measure particles immediately after filtration because larger particles can form if samples are stored overnight before testing. For vaccines adsorbed to alum, or for live-attenuated bacteria that can’t be filtered, SVPs are monitored for product consistency and stability of intended particles.

Validating MAM: A typical strategy from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) for quantitative methods to assess purity, impurity, and identity is used for qualifying MS-based MAMs. Initially, both UV and MS data are collected until transfer to QC and validation, then only the MS signal is collected. Optimization and validation of robustness of that method (instrument-to-instrument and site-to-site) are critical for QC applications.

Amgen’s strategy was to assess robustness for one MAb and apply that method to other MAbs (use of platform method data sets). Technology transfer to QC required close collaboration and training for analysts to use the instrument and software. Running a product reference standard concurrently is vital to enable detection of new peaks in test samples. System suitability criteria were placed on relative retention time and on peptide-fragment–mass accuracy using control chart trending of multiattribute data from the reference standard.

MAMs have been used for drug-substance and drug-product release testing and for stability testing. MAMs can monitor sialylated glycans, and a good correlation with a glycan map is obtained. Tamer Eris mentioned that Amgenʼs MAM assay has yet to be implemented globally (e.g., for retesting in the European Union), but that is the plan.

Session Two: Drug Product Comparability
The afternoon session on day one featured three perspectives on approaches to and expectations about comparability. One common thread for the presentations was the seemingly universal nature of how principles of risk assessment and thoughtful evaluation of proposed changes should drive comparability study design. A sound, science-based approach to drug product comparability essentially is the same as that used for drug substance comparability.

Comparability Assessment and Protocol: Ingrid Markovic (CBER) presented the agency’s overall perspective on best practices and points for sponsors to consider when undertaking comparability assessments for complex biologics. She also discussed the benefits of comparability protocols in managing postapproval changes. Markovic first outlined the regulatory guidelines on that topic (7–10), emphasizing that a demonstration of product comparability using a panel of analytical and biological testing generally is sufficient. Comparability assessment should require nonclinical or clinical data only if it cannot be concluded that observed differences between pre- and postchange materials would have no effect on safety and efficacy. As is the case with many aspects of product development, the expectations and formality of comparability assessment increase as a program progresses from phase 1 to postapproval stage.

Markovic then touched upon unique aspects of comparability for several modalities under CBER jurisdiction. For cell therapies, variability and scarcity of cellular source materials make it difficult to assess comparability during development. The potential for multiple mechanisms of action can confound assignment of CQAs, and the absence of reference standards and the limited expiry of products pose further challenges. One solution to mitigate that uncertainty is a strategy known as split manufacturing, in which a single lot of source material is divided and processed in parallel all the way to final drug product by both the prechange and postchange processes, enabling a head-to-head comparison of product quality. By contrast, comparability assessments of coagulation-factor drug substances and drug products more closely resemble those of purified-protein biologics.

With respect to changes limited solely to a drug product itself, Markovic presented two case studies of vaccines reviewed by CBER in recent years. The first case considered a postapproval change to the materials of construction of a container–closure system. The second case involved a change from a liquid to a lyophilized drug product. The FDA’s expectations for comparability of both products were much like those for protein biologics: product compatibility data, extractables and leachables assessment, container–closure integrity testing, release testing for at least three consecutive commercial lots, and comparative stability data. For a container–closure change, partial long-term stability data might be acceptable when justified and supported with accelerated stability comparability data. However, to support a change in the state of a dosage form (e.g., liquid to lyophilized), additional drug product physicochemical and biological characterization is warranted to demonstrate that lyophilization does not compromise drug safety or efficacy.

Regarding postapproval changes, Markovic reported that sponsors’ increasing use of comparability protocols (CPs) has been highly beneficial both for companies and for CBER. Per 21 CFR 601.12(e), companies can submit a CP to describe the nature of upcoming process or product changes and assessments that will be conducted to demonstrate comparability. Upon FDA approval of that CP, subsequent supplements covering those changes might have reduced regulatory reporting requirements (provided that the postchange material is deemed comparable per the terms of the protocol). Because CPs work best with well-defined process or product changes with limited risk, they are useful particularly for drug product changes such as container–closure systems, fill–finish site transfers, and facility and equipment upgrades. Between 2004 and 2014, nearly 90% of the CPs reviewed by CBER enabled postapproval changes to become effective through the far-more-rapid “changes-being-effected in 30 days” (CBE-30) or CBE-0 supplement (at the time of distribution) submission pathways.

Those represent a substantially quicker path to implementation for a commercial product than a postapproval supplement (PAS). The CP concept is shaping up to be a key element of the ICH Q12 guideline, which will enable the use of postapproval change management protocols (PACMPs).

Comparability of Novel Therapeutics: Frank Maggio (Amgen) presented his company’s experiences in conducting comparability studies for two novel therapeutics. He illustrated the complexities of assessing drug substance and drug product changes for unique modalities. In the first case study, Maggio discussed the comparability strategy for blinatumomab, a bispecific T-cell engager comprising two antibody variable domains connected with a linker. He explained that in later stages of development — when batch history was more extensive (at least five data points available) — statistically derived acceptance criteria for comparability were calculated (e.g., TIs) and used for most attributes. In some cases, less batch data was available because of limited assay experience or manufacturing history. For those cases, Amgen justified leveraging data from all earlier iterations of its manufacturing processes based on the small changes and comparability to the prechange process in effect at the time of the study.

Maggio shared that the assessment of the final commercial blinatumomab lyophilized drug product revealed only three differences with the phase 2–3 material, none of which affected efficacy or safety. SVP counts for species 10 μm were higher for the postchange drug product when measured using light obscuration. But orthogonal analysis by flow imaging microscopy confirmed that this observation largely was caused by variations in silicone oil microdroplet content, not proteinaceous particles.

Statistically significant differences also were observed in levels of acidic species by cation-exchange HPLC (lower levels) and melting temperature by differential scanning calorimetry (higher levels). However, those differences were attributable to improvements in product quality resulting from higher drug substance purity and a small increase in an excipient concentration in the commercial product, respectively. Further evidence of comparability was provided by data from a drug-product photo-stress study, which showed highly comparable rates of degradation over seven days.

Maggio’s second case study was about the oncolytic gene therapy product talimogene laherparepvec, an attenuated herpes simplex virus type 1 (HSV-1). The virus infects, replicates within, and lyses certain melanoma cells while expressing human granulocyte-macrophage colony stimulating factor (GM-CSF) to potentially direct a systemic T-cell response against a tumor. The complexity of the drug’s biology and the temporal interrelationship between its two different mechanisms of action made comparability difficult to fully evaluate fully without resorting to nonclinical pharmacokinetic (PK) and pharmacodynamic (PD) studies. Therefore, at each stage of development, physicochemical and extensive biological in vitro comparability testing were supplemented with head-to-head xenograft mouse studies to demonstrate comparable safety and efficacy. Those data proved to be key in addressing observed differences in drug substance glycoprotein content.

The role of drug product stability in comparability assessment also evolved as talimogene laherparepvec product development progressed. In early stages of development, drug product comparability was evaluated by assessing stability trends visually during long-term storage conditions only. Later in development, both long-term and limited accelerated stability data were used. A final commercial comparability study used extensive accelerated and stressed drug-product stability data on multiple prechange and postchange drug product lots. Overall, the case of the oncolytic gene therapy product with multiple changes, limited batch data, and complex biology, was not amenable to statistical comparability analyses.

Critical Raw Material Control in Drug Substance Affecting Drug Product: In the final talk of the session, Eran Benjamin (Eli Lilly) presented a case study in which a change to a critical raw material in drug substance manufacturing prompted an assessment of drug product comparability. To enable commercialization of a PEGylated protein for treating diabetes, Lilly needed to introduce two additional PEG reagent suppliers before phase 3. Polymer attributes such as PEG length and polydispersity were critical to product performance, but the manufacturing processes used by the three suppliers each delivered slightly different profiles. Benjamin described how Lilly evaluated the PK implications during drug substance comparability studies. Those studies showed that differences in average molecular weights of the PEGs would not cause premature clearance of the drug. But additional studies were required on the drug product to determine that PEG reagent source did not have an adverse effect on stability.

Limited drug product batch history through phase 2 clinical development precluded the setting of statistically determined comparability criteria. Thus, the Lilly team based its assessment on a comprehensive set of characterization assays and accelerated stability data in addition to in-process and release test results. Accelerated stability studies proved to be especially useful and demonstrated that degradation profiles and potency levels were comparable among drug product lots generated from the three different PEG sources. Benjamin also shared that as a follow-up, the team conducted a subgroup analysis of phase 3 clinical data, which determined that differences in PEG source had no effect on PK, PD, and safety in patients.

Benjamin shared a lesson learned during his team’s preparations for commercial drug product manufacturing. To accommodate first-in, first-out use of drug substance batches for drug product manufacturing, the commercial drug product control strategy needed to allow for mixing of drug substances from more than one PEG supplier. Robust analytical tools were implemented at the PEG manufacturing site to ensure good control of polymer attributes. But upon testing the final blended drug product by cation-exchange chromatography, the team encountered assay failures. Drug products containing two different PEG sources yielded previously unseen peak doublets because of modest differences in polymer molecular weight. That finding prompted a slight tightening of the PEG manufacturer’s molecular weight specifications and a follow-up study comparing drug products filled with single-sourced PEG drug substance and those filled with blended drug substance lots. With the additional raw materials controls in place, subsequent analysis of accelerated stability samples showed that all permutations of drug substance blends were comparable to single-sourced materials and to each other, thus enabling supply chain flexibility in drug product manufacturing.

Panel Discussion: Drug Product Comparability
For the panel discussion on drug product comparability, session speakers and cochairs were joined by Deborah Schmiel of CDER/FDA, Sean Walsh of Advaxis Immunotherapies, and Chandra Webb of Pfizer.

Comparability Study Design, Test Selection, and Criteria: In general, panelists agreed that the principles of design for drug product comparability studies did not differ much from the approach that would be used for a drug substance. Comparing three prechange batches with three postchange batches is well accepted for late-stage and postapproval products. But for early stage programs, having a number of batches to study might not be realistic. The proposed process or product changes should guide where emphasis is placed in this assessment. For some changes, release and stability tests may be sufficient to demonstrate drug product comparability. The selection of additional characterization tests and acceptance criteria ought to reflect the degree of risk that the changes can pose to CQAs.

Similarly, the panelists agreed that setting of comparability acceptance criteria did not lend itself to a one-size-fits-all approach. For drug products with extensive manufacturing history, statistical methods can provide well-justified benchmarks for postchange drug products to meet. But for cases in which manufacturing experience is limited or when developing acceptance criteria for bioassays rather than chemistry assays (which often differ in method accuracy and precision), applying a single statistical tool across all product quality attributes rarely makes sense. In setting acceptance criteria, sponsors should consider assay performance, extent of manufacturing history, and criticality of an attribute itself. Failure to do so can lead to finding statistically significant differences between drug products that have no meaningful effect on efficacy, safety, or comparability.

A unique aspect of drug product comparability is that drug substance lots of different ages and levels of degradation can be used in drug product manufacturing. That can confound efforts to assess comparability of drug products because it may be difficult to attribute elevated amounts of degradation products to a drug product or the associated drug substances used. In such scenarios, documenting the levels of drug substance degradants before drug product manufacturing can be highly valuable. Alternatively, drug product comparability acceptance criteria for certain attributes can be expressed in terms of maximum allowable change upon going from drug substance to drug product.

Postapproval Comparability Protocols: To CP or Not to CP? Following Markovic’s presentation, the panel discussed the benefits and limitations of submitting CPs to the FDA to facilitate postapproval change review and implementation. Both CBER and CDER reported very positive experiences with sponsors submitting CPs to cover relatively simple and foreseeable changes to product manufacturing. CBER’s trans-BLA (biologics license application) mechanism also has proven to be highly effective for enabling simple changes across multiple products. However, the panel warned attendees that as the complexity of a proposed change increases, the less amenable that change may be to coverage under a CP. Multiple changes that compound the risks of yielding a noncomparable product (e.g., a drug product site change coupled with a drug substance process scale-up and a new master cell bank) ought to be submitted for review as a PAS.

CDER noted in particular that attempts to manage complex comparability scenarios under a CP often prompts the department to issue numerous information requests to sponsors, asking for extensive data to gain confidence in the company’s rationale behind the CPs themselves. Moreover, submitting CPs for new manufacturing sites requires a process validation data package and a preapproval inspection.

Comparability Considerations During Development: Changes in drug product presentation are common as a program advances from early to late-stage development (e.g., from a lyophilized vial to a liquid or from a vial to a prefilled syringe). FDA panelists noted that they expect certain CQAs to be incomparable between the two presentations. Impurity levels might differ, shelf lives might be shorter, and a change in container–closure system can yield differences in SVP profiles. But regulators appreciate that such changes bring more convenience to patients, and authorities have noted that there is more latitude in comparability assessment when clinical experience will be gained with the new dosage form before BLA filing.

Programs that are granted breakthrough-therapy designation (BTD) present unique drug product lifecycle challenges. Such programs advance under expedited development based on compelling early phase clinical results. Sponsors need to weigh the risk of advancing a suboptimal drug product into pivotal trials and commercialization against the risks of reliably supplying a quality product to the market, which is a requirement under BTD. The panel advised sponsors to think about comparability and product–process changes carefully and early.

Part Two
The conclusion of this article will be published in the April 2021 issue of BioProcess International. It will include a summary of the discussions on drug product process validation and lifecycle management of legacy products.

References
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Disclaimer
The content of this manuscript reflects discussions that occurred during the CMC Strategy Forum. This document does not represent officially sanctioned FDA policy or opinions and should not be used in lieu of published FDA guidance documents, points-to-consider documents, or direct discussions with the agency.

Corresponding author Zahra Shahrokh is chief development officer at STC Biologics, 330 Nevada St, Newton, MA 02460. Andrew Weiskopf is vice president of CMC Regulatory Affairs at Sana Biotechnology. Yves Aubin is a research scientist at Health Canada. David Allen is a research fellow at Eli Lilly. Natalya Ananyeva is a team lead at CBER, FDA. Julia O’Neill is a distinguished fellow at Moderna Therapeutics. Nadine Ritter is president and analytical advisor at Global Biotech Experts, LLC. At the time of this conference, Siddharth Advant was executive director of biologic manufacturing at Celgene. Howard Anderson (posthumous) was team lead, Office of Biotechnology Products, CDER, FDA.