Integrating CMC Document Preparation into the Development Process for Vaccine INDs

Many of the development activities leading to the filing of an Investigational New Drug Application (IND) for a new vaccine are carried out in parallel: For instance, fermentation and cell culture, purification, formulation, and analytical testing and characterization are all moving forward at the same time. Scientists often approach these activities sequentially: run the experiments, develop the process and assays, then prepare and test clinical supplies, saving all writing tasks until last. But a sequential approach increases the difficulty of preparing an IND and typically causes filing delays. To minimize the preparation time required for the chemistry, manufacturing, and controls (CMC) section of the IND, writing and document preparation should be integrated with the other development activities and coordinated by experienced technical writers and editors.

Process Development Activities

Development activities can be divided into four interdependent categories that apply to all phases of clinical trials: process, analytical, and formulation development; manufacture and testing of preclinical supplies; manufacture and testing of clinical supplies (prepared under CGMP regulations); and preparation of CMC documentation for the IND.

Many of these activities are carried out in parallel (Figure 1), and effective interaction among groups and departments is essential, not only for the development of a successful process, but also for the preparation of a high-quality CMC section for the IND.

Biologics and vaccines are complex products, with a complicated path of process, analytical, and formulation development. Significant development work is required to scale up the process, finalize the formulation, and validate the assays in preparation of a manufacturable product at commercial scale. So a balance must be struck between rapidly providing material for clinical evaluation using an interim process, and delaying clinical trials until the final process, formulation, and assays are available. For each clinical trial phase, a decision needs to be made about when to halt process development and establish a fixed process for the preparation of clinical materials.

Table 1. Milestones in the document preparation process for the chemistry, manufacturing, and controls (CMC) section of an Investigational New Drug Application (IND).

The goal should be to prepare phase 3 clinical materials using the final process. The product and process development are documented in the IND and successive amendments, and all of this information is ultimately compiled for the pharmaceutical development section of the future marketing application.

CMC Document Content

A significant amount of information is required for the CMC section of an IND, particularly for a late-phase clinical trial (1–3). In the European Union, a new clinical trial directive (4) for Clinical Study Authorization Applications (CSAs) has been issued, requesting CMC information similar to that needed for a U.S. IND but which uses the Common Technical Document (CTD) format (5). The regulatory requirements for vaccines are stringent, particularly for late-phase trials, because these products could be administered to large numbers of healthy infants, children, and adults; this is reflected in the information required.

Because vaccines are generally derived from biological systems, detailed information is provided on their initial derivation or isolation and on the preparation of their master and working seeds and cell banks as appropriate, including a discussion of raw materials. Although a number of newer vaccines can now be considered well-characterized biotechnology products, extensive characterization data are not generally available until late in the development phase.

Figure 1. The vaccine development process: Basic research develops the initial product, process, formulation, and assays, which are then further developed and scaled up before each clinical campaign. Material for clinical trials is prepared under CGMP conditions. Information from all of the functional areas is included in the IND.

As a result, process descriptions can be important in defining the product. Some of the assays - particularly those used for measuring potency - can be complex. The process, assays, and formulation can change between early and late development as the amount of information acquired on the product increases. These changes need to be documented in the INDs in successive amendments for each new set of lots provided to the clinic.

As part of the ongoing product development program, additional guidelines such as those listed in the "CMC Document Guidance Resources" sidebar should be studied.

The flow of required information can come from many functional areas (Figure 2) and requires coordination by a technical writer or editor. The complexity of information and the number of groups involved increase significantly as the process moves into the final phases of development and toward transfer to a manufacturing facility (6,7). Participants and experts from all the contributing departments are expected to carefully review the document. The regulatory affairs department is additionally responsible for ensuring that the document is consistent with previous communications to the agencies concerned and is consistent with clinical and preclinical documents.

Ensure sufficient documentation. Regulatory agencies raise questions if appropriate content items are not present or are inconsistent throughout the document and if insufficient details or data are provided on the manufacturing process, sample testing, or bulk and final container stability. European agencies in particular require a significant amount of information on raw materials of animal origin and on their use in the process, as well as in the preparation of master seeds or cell banks. Additional country-specific requirements within the European Union (based on questions asked previously) should also be taken into consideration. However, to facilitate document preparation and submission tracking, the number of document versions relating to specific countries or regions needs to be kept to a minimum.

The level of detail required in process and analytical descriptions is often subject to internal debate and can result in agency questions. Sufficient detail must be provided so that the agency reviewers can understand and evaluate the process. However, if excessive detail is provided, every minor change to a noncritical process or test parameter will require discussion in a future amendment. The specifications for key parameters should be set carefully. Agencies may request justification for broad initial specification ranges.

Figure 2. Flow of information for IND preparation: The required information is obtained from numerous sources to assemble a draft CMC section, which is submitted for review. Once the testing is complete, an analytical report is prepared for each lot, and this information is included in the CMC section along with the final stability data. The final audited CMC section is then ready to be submitted to regulatory agencies.

Consistency throughout the document is critical. The names of intermediates and samples should be the same in the upstream and downstream process descriptions and in the analytical sections. The level of detail in process descriptions and flow diagrams should be consistent in both "Drug Substance" and "Drug Product" sections. If one section is too detailed, it could raise questions in the other section that might not otherwise be raised. Sampling locations for analytical testing should be indicated on flowcharts and should be consistent with the samples listed in analytical descriptions.

In the case of an amendment, changes made since the original submission can raise questions if the level of detail is not consistent within the amendment or with the original submission. As part of the planning process, the technical writer or editor should provide a terminology list to the authors, as well as guidelines on format and level of text and flow diagram detail; this will streamline the preparation of the document and reduce agency questions related to clarity and consistency.

The Writer's Role in Document Prep

A technical writer or editor manages the entire document preparation process and should be involved in or aware of any technical discussions leading up to the preparation of clinical lots. For a new IND, the technical writer or editor leads planning meetings to discuss the content and level of detail in the CMC section and assigns authors and auditors. A technical writer or editor who has experience with the preparation of documents for multiple projects and fielding the resulting questions from regulatory agencies can provide substantial guidance during the planning stages - which can shorten the preparation time for these documents. The internal review process is also streamlined (and the number of comments is reduced) when the technical writer or editor works with the authors and technical experts on the required content and level of detail, edits the early drafts, and provides feedback to the authors.

A Product Review Template from the New Draft Guidance for CMC Reviewers of INDs (Somatic Cell Therapy)

The writer's tasks include preparation and assembly of draft sections and, for large or complex documents, coordination of several review cycles, each one followed by editing and auditing (Table 1). The timing of these steps can vary widely - from a simple product in an early-phase trial to a complex product in advanced-stage trials. The timing can also be modified during document preparation if significant comments are obtained or if new issues arise. An additional review cycle can be added for the entire document if needed, or specific sections (new or rewritten) can be reviewed separately.

Because many development activities occur in parallel with document preparation, the technical writer or editor should be aware of new issues and address them throughout the document. Stability data and certificates of analysis are not usually available until the end of the document preparation process; they should be inserted as soon as they are available. For IND amendments or for CSAs that contain information previously submitted in an IND, the process becomes less labor-intensive, and the timelines can be shortened significantly.

During the editing phase, the technical writer or editor should collate and tabulate comments from all reviewers and document comment resolution. The resulting editing tables should be circulated to the reviewers and relevant functional areas to ensure a transparent review process. Consensus meetings should be held as necessary to resolve any complex issues and to review any significant changes to the document. Managing the process this way ensures that all changes are appropriate. After auditing, the final CMC section is ready to be submitted to regulatory agencies.

Technical writing skills. To ensure that the CMC section clearly and accurately communicates the necessary information, the technical writer or editor should have an excellent command of the English language as well as experience in vaccine development. Subtleties of diction and sentence structure or misuse of technical terms can significantly alter the meaning of a passage, particularly for concepts such as timing, intention, or cause and effect. Moreover, an inconsistent writing style can be distracting to agency reviewers. The style and format should be consistent despite the contributions of many authors.

CMC Document Guidance Resources

Consistent nomenclature (using the same sample names and abbreviations for analytical and process sections, for instance) should be developed at the planning meeting. The desired format, style, and layout of the individual contributions should be defined in a style guide, which can be specific for each large document. For smaller documents and to resolve minor issues, a common style guide should be used for all contributing departments. The ACS Style Guide (8) is appropriate for CMC sections.

Before submitting the finished document to regulatory agencies, it should be checked for accuracy by an independent quality assurance group. To facilitate that audit, the technical writer or editor can work with the authors to ensure that source documents are available to support all of the data and statements. The technical editor should also reword general statements that can be cumbersome to verify so they match the documentation available.

Tech Writers Improve INDs

The development process for vaccines is intricate because of their biological origin and complexity. The guidelines for IND content and for similar documents worldwide require a significant amount of information be submitted to regulatory agencies. As a result, preparation of CMC sections for vaccine INDs is a complicated process and requires a technical writer or editor to lead the planning, assembling, reviewing, and editing to ensure a consistent and high-quality document. Experience with the preparation of multiple vaccine INDs or CSAs and the resulting questions from worldwide regulatory agencies increases the cumulative knowledge of technical writers and editors, which improves the quality of future submissions for other vaccine products.

References

(1) CBER,

Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products

(FDA, Rockville, MD, November 1995).

(2) CBER, Draft Guidance for Industry: INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology-Derived Products - Chemistry, Manufacturing, and Controls Content and Format (FDA, Rockville, MD, February 1999).

(3) CBER, Guidance for Industry: Content and Format of Chemistry, Manufacturing, and Controls Information and Establishment Description Information for a Vaccine or Related Product (FDA, Rockville, MD, January 1999).

(4) Directorate General for Enterprise, Detailed Guidance for the Request for Authorisation of a Clinical Trial on a Medicinal Product for Human Use to the Competent Authorities, Notification of Substantial Amendments and Declaration of the End of the Trial, ENTR/FS/BL D(2003) (European Commission, Brussels, Belgium, April 2003).

(5) ICH Steering Committee, Common Technical Document for the Registration of Pharmaceuticals for Human Use, CPMP/ICH/2887/99 (Geneva, Switzerland, November 2000). Also Federal Register 66(200), 52634–52637 (16 October 2001).

(6) Goochee, C.F., "The Roles of a Process Development Group in Biopharmaceutical Process Startup," Cytotechnol. 38(1–3), 63–76 (2002).

(7) Gerson, D.F. et al., "Transfer of Processes from Development to Manufacturing," Drug Inf. J. 32, 19–26 (1998).

(8) The ACS Style Guide: A Manual for Authors and Editors, 2nd ed., J.S. Dodd, Ed. (American Chemical Society, Washington, DC, 1997). BPI