Biologics and Manufacturing Changes

Biologics and Manufacturing Changes Richard M. Lewis, PhD and Mary Ellen Cosenza, PhD, DABT, RAC 24

Historically, biological products were defined by the process that produced them. Biochemical methods were inefficient in defining a wellcharacterized material, so the manufacturing methods themselves were tightly controlled to ensure the production of a product consistent with the one used throughout clinical trials and demonstrated to be safe and effective. By definition, this implied that a change in the process might also change the product. Although biological products have become much better characterized over the last couple of decades, the manufacturing process is still an important component in defining the product. Changes in manufacturing methods, such as site changes, scaling up capacity, improving Good Manufacturing Practice (GMP), and increasing purity, cost-effectiveness and yield, will affect manufacturers of all drug products at some time over their lifetime. 1 Regulatory Guidance Recognizing the need of manufacturers to change processes, regulatory agencies have offered guidance (see Table 1). In 1996, the US Food and Drug Administration (FDA) presented initial advice in Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products. 2 FDA guidance is based on Title 21 Code of Federal Regulations (21 CFR), Sections 314.70 and 601.12. The International Conference on Harmonisation (ICH) also addressed the need to characterize manufacturing changes in Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, Q5E 2005. 3 In addition, the European Medicines Agency (EMA) has offered two guidelines for characterizing products after manufacturing changes. 4,5 In all of these guidance documents, the term comparability is used to differentiate the exercise (or demonstration) from one of equivalence or identity. There is recognition of changes in manufacturing that result in minor changes in the product without changing safety, purity or effectiveness. Thus, there must be a demonstration that the products are highly similar, i.e., not requiring molecular identity, but providing assurance that there is no adverse impact on quality, safety and effectiveness. Although there is overlap in many of the biochemical and regulatory principles governing comparability and biosimilarity, the discussion in this article is limited to the comparability of product before and after a manufacturing or process change made by a single manufacturer. Manufacturing Change can be Associated With Molecular Change Experience has shown that changes in manufacturing can lead to product changes. Small changes can result in major changes in the molecule and seemingly larger changes can result in minimal change to the product. Biological products are very complex molecules with primary, secondary and tertiary molecular configurations that define their activity. Activity can be expressed as enzymatic, receptor-agonist or antigen-binding. The antigen-binding of a monoclonal antibody may result in an expression of activity through antibody-dependent cytotoxicity, complement activation or other molecular activity that relies on a portion of an antibody for either binding or increased circulation and exposure. Because the association between specific molecular characteristics (critical quality attributes or CQAs) and clinical performance are not always known, characterization beyond biochemical evaluation is often required. Changes in molecular conformation attributed to minor manufacturing changes can result in differences in immunogenicity, pharmacokinetic/pharmacodynamic (PK/PD) and even activity. Similarly, changes in molecular glycosylation characteristics can be very important for PK/PD, solubility, biodistribution, bioactivity and other changes associated with conformational change. Changes in glycosylation can be related to structure, amount and location. Development of a Comparability Program A number of factors need to be considered in the development of a comparability program, including the type and scope of changes, such as cell line or process changes; manufacturing site changes or formula changes; the stage of development, e.g., after Phase 1, in Phase 3 or postmarket; and the amount and depth of historical manufacturing data. We presented a number of examples of manufacturing changes previously. 6 There is a hierarchy to the data included in comparability assessments (see Table 2). This order is 1) analytical, 2) nonclinical pharmacokinetics (PK) and pharmacodynamics (PD), 3) nonclinical toxicology, 4) clinical PK and PD and 5) clinical safety and efficacy. In all evaluations, the analytical comparison of the products is central and often determines the extent of additional data that may need to be developed for the demonstration of comparability. These can include novel testing methods and stability data. Accelerated stability and degradation studies are often very useful. This hierarchy notwithstanding, in practice, most comparability programs are the result of a risk management approach 7 and often a number of studies are done in parallel. The determination of risk of manufacturing changes based on CQAs, referred to as Quality by Design, has been publicly discussed 8 and FDA has requested data submission to a pilot program evaluating such programs. 9 Regulatory Focus 25

technology will help to guide decision making for design of the analysis. Most comparability determinations are based upon analytical data. In addition, the results of analytical testing will contribute to the decision to provide additional in vivo testing. In all comparability determinations, analytical comparisons will be an important component. Pharmacokinetics Nonclinical animal data may include PK and bridging toxicology and, if appropriate, additional toxicology studies. Selection and availability of relevant species are important in determining which data will be useful. Characteristics of the target animal species to consider include amino acid sequence homology, mechanism of action, pharmacologic homology and whether or not the target is expressed only in the disease or in different levels during disease manifestation. When studies are done in relevant species, there is binding to target that may prolong the t 1/2, may lower the C max and alter the distribution. There is no specific requirement that PK studies meet the bioequivalence standard: area under the curve (AUC) and C max to have geometric means of 80% 125% with a 90% confidence interval. However, in either animal or human trials, comparability data that meet this standard are more convincing. The nature of the product and the class of the molecule, its mechanism of action and other previous data, e.g., nonclinical and clinical information, should be considered along with the frequency and route of administration, dosing and the specific patient population. When possible, the variability of a particular characteristic will help to determine the acceptability range for the new product. Analytical Data The development of the analytical data should include a comparison of release testing but the comparison should go further and be much more in depth. The activity and the molecular characteristics associated with that activity should be the focus of comparisons. A manufacturer s knowledge of the CQAs or the platform Clinical Comparability A number of trial designs crossover, parallel or sequential might be useful in comparing product made before and after a change in manufacturing. Each has advantages and disadvantages. When manufacturing changes are implemented late in development, such as during or after Phase 3 trials, PK/PD data will probably be needed and there should be an attempt to power the trial for bioequivalence. Failing to demonstrate comparability with a clinical PK/PD trial may necessitate additional safety and efficacy data using product manufactured with the new process. Immunogenicity Immunogenicity limits the use of many animal models for large biological molecules and Table 1. Regulatory Guidance Concerning Comparability for a Manufacturing Change Guidance Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products, 1996. Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, 2003. Guideline on Comparability of Medicinal Product Containing Biotechnology-Derived Proteins as Active Substance. Non-Clinical and Clinical Issues, 2003. ICH Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, 2005. Reference 2 3 4 5 26

Table 2. Information for Comparability Testing Increases from Analytical to Clinical Safety and Efficacy Testing Hierarchy Analytical Molecular characterization Stability testing Accelerated/ degradation Real time Biological potency assays Animal pharmacokinetics/pharmacodynamics Preclinical animal toxicology Human pharmacokinetics/pharmacodynamics Human safety and efficacy will also limit their usefulness for comparability testing. Nevertheless, possible changes in immunogenicity should be addressed. Because immunogenicity can affect PK and has been shown in some instances to prolong elimination and in others to prolong circulating levels, changes must be addressed. The highest level of concern is the possibility of antibodies cross reacting with autologous molecules. Comparability Demonstration During Development Manufacturing changes are often made during product development. The hierarchy noted previously increases in parallel with the stage of development as well as with the magnitude of the change. Since more manufacturing data have been accumulated by the later stages of development, the demonstration of comparability should be more stringent and regulatory agencies will expect a larger body of data. From the riskmanagement perspective, changes made later in development offer higher risks than those implemented earlier. Therefore, more-stringent comparability criteria are likely for a product later in the course of development from both a regulatory and scientific perspective. Prior to Phase 2 If toxicological effects are not associated with product activity and may be related to impurities have been documented, some additional toxicology testing on the new product may be needed. The identification of relevant species for comparison testing will contribute to the decision of comparability. It may have been previously determined that animal PK in a relevant species is similar to human PK. If an animal PK comparison demonstrates comparability, there may not be a need for human studies. However, clinical PK studies may be needed depending upon the analytical data and the availability of a relevant species. Prior to Phase 3 Comparability studies at this stage of development will usually require clinical PK/PD comparisons. Ideally, these studies should meet bioequivalence standards. During Phase 3 or Immediately Prior to Approval Because Phase 3 trials are pivotal and product approval depends upon their successful outcome, manufacturers are encouraged to implement product changes either before initiation of Phase 3 or after marketing approval. Any changes to the product that might affect the evaluation and analysis of the study results should be avoided. However, if a manufacturing change is significant and unavoidable, the comparability demonstration will likely include animal PK, clinical PK/PD and, in some cases, clinical safety and efficacy data for product made using the new process. After Marketing Approval Because the history of manufacturing will have been developed by postmarket, all components of the comparability exercise will be more stringent. In analytical data development and PK comparisons, acceptance criteria are likely to be narrower. Regulatory agencies often rely on historical trends in safety data developed after marketing. Changes in manufacturing that can alter historical trends may be difficult to accept. Unfortunately, failure to demonstrate comparability may result in an agency determination that the manufacturing change results in production of a different product. Thus, the new product will need to be supported with specific safety and efficacy data and the ability to rely on previously developed data may vary. Conclusion Manufacturing changes are inevitable over the lifetime of biological products. The implementation of changes requires a thoughtful and thorough approach. Planning should be done well in advance of the change and commitment to a particular change should depend upon the outcome of comparative data. In particular, sufficient material from most steps of the historical process should be set aside for comparative purposes. The complexity of the comparability program increases as development progresses; changes during Phase 1 will require less rigorous data than changes made before Phase 3. If possible, changes should not be implemented during Phase 3. Most manufacturing changes will have some effect on a biological molecule. Knowledge of the product and its critical quality attributes, results of testing over the lifetime of the product and the 28

molecular characteristics associated with clinical activity should be the focus during preparation for comparison testing prior to implementation of a manufacturing change. This knowledge rests with the manufacturer and will form the basis for the initial analytical testing and the establishment of new specifications. References 1. Guidance for Industry Q8(R2) Pharmaceutical Development. FDA website. http://www.fda.gov/downloads/drugs/ ucm073507.pdf. Accessed 25 January 2011. 2. Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products, 1996. FDA website. http://www.fda.gov/drugs/ ucm122879.htm. Accessed 25 January 2011. 3. Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, Q5E 2005. FDA website. http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/ucm128076.pdf. Accessed 25 January 2011. 4. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: quality issues, 2003. EMA website. http://www.ema.europa.eu/docs/ en_gb/document_library/scientific_guideline/2009/09/ WC500003573.pdf. Accessed 25 January 2011. 5. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance. Non-clinical and clinical issues, 2003. EMA website. http:// www.ema.europa.eu/docs/en_gb/document_library/ Scientific_guideline/2009/09/WC500003963.pdf. Accessed 25 January 2011. 6. Lewis RM, Cosenza ME. Summary of DIA Workshop: Comparability Challenges: Regulatory and Scientific Issues in the Assessment of Biopharmaceuticals. Drug Information Journal. 2010; 44(4): 485-504. 7. Guidance for Industry Q9 Quality Risk Management. http://www.fda.gov/downloads/drugs/ ucm073511.pdf. FDA website. Accessed 25 January 2011. 8. Mire-Sluis A et al. Quality by Design: The Next Phase. BioProcess International. 2009; 7(1): 34-42. 9. Submission of Quality Information for Biotechnology Products in the Office of Biotechnology Products; Notice of Pilot Program. Federal Register website. http://federalregister.gov/a/e9-22378.accessed 25 January 2011. Authors Richard M. Lewis, PhD, is the chief executive officer of Access BIO LC, a biopharmaceutical consulting company that focuses on assisting clients with comparability, CMC, preclinical toxicology and regulatory issues to support clinical development. He previously spent 15 years at the US Food and Drug Administration s Center for Biologics Evaluation and Research. Mary Ellen Cosenza, PhD, DABT, RAC, is executive director of international regulatory affairs and safety for the emerging markets at Amgen Inc. She has more than 27 years experience in the biopharmaceutical industry including the fields of toxicology, compliance and regulatory affairs.. Regulatory Focus 29