Changes to an Approved Product Chemistry, Manufacturing and Controls By Khandan Baradaran, PhD and Peggy Berry, MBA, RAC It is a huge achievement for any company to obtain licensing rights to an approved pharmaceutical product. Postapproval challenges are inherent in the marketing and distribution process. Of these, foreseen and unforeseen changes to the manufacturing process top the list. Sponsors of newly licensed products may encounter issues that were not fully realized during development, such as long-term stability issues, which only come to light within the first two years postapproval. Such unforeseen issues require corrective actions that usually impact the approved manufacturing process in one or more ways. At the same time, there are likely to be foreseen, legitimate needs to make changes to the approved product or production process. Postapproval changes can be relatively minor, such as like-for-like changes to manufacturing equipment; or they can be more critical, such as a change to the drug product container closure. The latter is common for products that undergo lifecycle management. For example, the company may, develop and obtain approval for the drug supplied in a vial, then plan to obtain approval for a prefilled syringe presentation for ease of patient use. Certain changes must be reported to regulatory authorities, and in some instances, the 30 April 2008
sponsor may be prevented from distributing the drug manufactured with a particular change until the regulatory authority has reviewed and approved the change. In the US, manufacturing changes can be reported to FDA in supplements to the marketing/license application and in annual reports. The four reporting categories are: prior-approval supplement (PAS), changes being effected (CBE), changes being effected in 30 days (CBE-30) and annual report (AR) (Table 1). Some changes are transparent to the license 1 and do not need to be reported. It is the regulatory professional s job to determine whether a change needs to be reported, and whether the regulatory agency needs to approve the change before distribution. This can be a complex task, involving extensive oversight, reporting and control within a company to identify a change, assess the impact to the drug product, tag out the impacted drug product lots until approval is obtained, and report the change to the relevant authorities. The complexity increases with more products in the manufacturing plant that may require changes, and marketing rights in multiple countries. In the US, licensed pharmaceutical drug manufacturers pay a postmarketing user fee to market the drug (see Prescription Drug User Fee Regulatory Focus 31
Table 1. Impact Assessment and Reporting of CMC Changes Degree of Change Impact Assessment Reporting Category Major change substantial potential to have an adverse effect prior-approval supplement (PAS) Moderate change moderate potential to have an adverse event changes being effected in 30 days (CBE-30) Certain moderate changes moderate potential to have an adverse event and FDA concurrence obtained for product distribution changes being effected (CBE or CBE-0) when supplement received Minor change minimal potential to have an adverse event annual report Act (PDUFA)). 2 Fees are collected from licensed pharmaceutical companies on a per-product (each approved dosage form) basis. Annual establishment fees and fees required for supplements with clinical information also apply. In return, FDA is required to review certain supplements within a specified time frame (four months for most PAS, 30 days for CBE-30); some supplements have no time constraints. Impact Assessment Each change must be assessed to determine whether it needs to be reported. Changes that must be reported include changes to the product, production process, quality controls, equipment or facilities established in the approved license application. 3,4 To assess a change, the regulatory professional must determine what potential adverse effects it could have on the product s identity, strength, quality, purity or potency as related to the product s safety or effectiveness. Which of the four reporting categories applies depends upon this product impact assessment. In addition to determining which submission type to file (based upon potential effect on product quality attributes), the impact assessment must include any repercussions for validation; equipment, the manufacturing process step, analytical methods or any combination Table 2. Major Changes (Substantial Potential of AE) Requiring Prior-approval Supplement Filing Process Changes change to validated sterilization process (sterile products) new/revised recovery procedures new/revised purification process, including column change change in process solution chemistry or formulation change in processing step sequence or processing step addition, deletion or substitution reprocessing a product without a previously approved protocol scale-up requiring larger fermenter, bioreactor or purification equipment (biologics) Changes to Analytical Methods Other Major Changes Triggers for Additional Clinical or Nonclinical Studies replacing an existing analytical method with a new one (e.g., RP-HPLC to replace ELISA) establishing wider specification limits deleting a specification or analytical method eliminating tests from the stability protocol assay transfer to another QC laboratory change in product composition or dosage form or ancillary components expiration dating period extension or change in storage temperature container/closure change change in manufacturing site conversion from single- to multi-product manufacturing area(s) culture growth time extension resulting in significant increase in cell doublings beyond validated parameters (biologics) cell line change or new MCB (biologics) formulation or excipient changes multiple simultaneous changes (e.g., scale-up, media components impacting titer, change in purification resin type, container closure) any change resulting in an observed change in activity assay (e.g., out-of-specification or trend regarding licensed specifications and manufacturing history) significant impurity profile increase 32 April 2008
Table 3. Moderate Change Examples (moderate potential of AE) Requiring CBE Supplement Filing Changes Being Effected in 30 Days (CBE-30) Changes Being Effected (CBE-0) addition of duplicated process change (e.g., fermentation) or unit process (e.g., purification column) with no change in process parameters manufacture of an additional product in previously approved multiple-product manufacturing area with same equipment/personnel if no changes in validated cleaning and changeover procedures additional release tests and/or tightening of specifications changing from one compendial test method to another replacing an in-house reference standard of quality systems may need to be revalidated. Validation data may need to be included in the submission package with the data that demonstrate comparability before and after the change. Submissions In the US, the waiting period when reporting can be reduced if a protocol for assessing and determining comparability is submitted and approved prior to any changes being made. The comparability protocol should describe the change or possible changes, planned testing and revalidation studies and conformance to prespecified acceptance criteria. This, in effect, allows a sponsor to obtain FDA agreement on what studies are expected when certain changes are made, and acceptable comparability outcomes. A comparability protocol should be filed with the initial marketing application or as a PAS. It allows FDA and the sponsor to agree on methods to be used to demonstrate comparability between the old and new manufacturing process, including: analytical methods and acceptance criteria stability data requirements 5 statistical tools nonclinical studies, if needed clinical studies, if needed Table 2 gives examples of major changes. Significant process changes, formulation changes, widening acceptance criteria, replacing analytical methods, scale-up and container closure changes typically require PAS. Triggers for additional clinical or nonclinical studies may include formulation changes or new excipients, significant changes to activity or impurity levels and, for biologics, cell line changes. Regulators are especially concerned about the potential immunogenicity impact of formulation or cell line changes for biologics. Certain moderate changes can be reported as CBEs. Sponsors may submit a CBE-0 or CBE-30, depending in part upon the impact assessment as well as discussions with FDA in advance of the submission to obtain concurrence on the filing strategy and timing of the change (Table 3). Some examples are the addition of a duplicate process chain or operation unit that does not impact licensed/approved process parameters, the addition of new products in the licensed manufacturing areas, changes to compendial test methods and the replacement of reference standards. CBE reporting is a rather gray area, and the reporting category may change depending upon the availability (or lack thereof) of agreements with FDA and internal strategic needs. Changes with the least potential for impacting product quality attributes should be submitted in the Annual Report (Table 4). These can include additional or morestringent release or stability specifications, more-stringent stability test parameters or time points, and modifications to analytical test procedures that do not change the basic test methodology or acceptance criteria. Drug substance and drug product stability trends and data are also included in the AR. Summary Postapproval changes to manufacturing processes and quality controls present unique challenges to licensed drug companies and must be assessed for their potential impact. The regulatory professional plays a pivotal role in assessing the change, obtaining feedback from regulatory authorities, and acting as the liaison between Table 4. Minor Change Examples (Minimal Potential for AEs) to File in Annual Report Annually reportable modification in analytical procedures with no change in basic test methodology or release specifications additional release tests and/or tightening of specifications replacing an in-house reference standard more-stringent stability test parameters or time points report of drug substance and drug product trend analyses (release and stability data) Regulatory Focus 33
the regulatory agencies and the in-house quality, manufacturing and supply chain groups. F REFERENCES 1. Sufficiently described in the license, such as a like-forlike equipment change. 2. For more information and to see the updated PDUFA 2007. Accessed 4 January 2008. www.fda.gov/oc/initiatives/advance/fdaaa.html. 3. Labeling change reporting requirements are beyond the scope of this article and are not discussed herein. 4. 21 CFR 314.70 and 21 CFR 601.12. 5. Stability data may be required for both API/drug substance and final drug product, depending upon the potential impact of the change to either. Additional Bibliographic Material 1. International Conference on Harmonization (ICH) Q5E: Comparability of Biotechnological Products Subject to Changes in their Manufacturing Process November 2004. 2. 21 CFR 314.70 (New Drug) 3. 21 CFR 601.12 (Biologic) 4. Changes to an Approved NDA or ANDA. FDA CBER/ CDER, April 2004. 5. Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products. FDA CBER/CDER, July 1997. 6. Comparability Protocols Protein Drug Products and Biological Products. FDA CBER/CDER, Draft September 2003. 7. Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology Derived Products. FDA CBER/CDER, April 1996. AUTHORS Khandan Baradaran, PhD, is a Senior Manager of Regulatory Affairs at Dyax Corp. Prior to joining Dyax, she held management positions in analytical development, quality control, quality assurance and regulatory affairs at Biogen Idec. Peggy J. Berry, MBA, RAC, is Senior Vice President, Quality and Regulatory Affairs at Dyax Corp., responsible for the strategic management and oversight of the quality and regulatory affairs departments. Previously she was director of regulatory affairs at AstraZeneca and managed the regulatory and clinical departments at Dey Laboratories. Berry also has worked for ILEX Oncology and Cato Research Ltd.) and in FDA review divisions. 34 April 2008