There are a number of reasons that your company might decide to utilize the services of an external regulatory affairs service provider. It may be appropriate to hire one with expertise in a type of product/technology when your company does not have that expertise in-house. One may be utilized when the workload of your internal Regulatory department is unusually high or while your company is interviewing to fill open regulatory affairs positions.

When your company uses contractors for development and manufacture of drug substances and/or drug products, data obtained from their facilities are included in any submission supporting investigational studies or product marketing. If the contractor has an internal CMC Regulatory Affairs department, it is important to liaise with them to obtain data for your dossiers and to ensure rapid identification of any development, manufacturing or stability issues that would impact your product registration. It may be valuable to have an independent Chemistry, Manufacturing and Controls (CMC) consultant evaluate the regulatory capabilities of contract development and manufacturing service providers and act as a liaison between your company and the contractor.

Once a decision has been made to consider using the services of a CMC regulatory service provider, it is important to identify the right one, establish a positive working relationship that includes communication and flexibility, clearly determine the expected deliverables and timelines, and rapidly identify issues that may arise during the course of the contract.

For the remainder of this article, the term “service provider” is used when referring to items that would be specific to an independent CMC regulatory consultant, “contractor” is used when referring to items specific to Regulatory Affairs staff associated with contract development/manufacturing companies, and “consultant” is used when referring to items that may involve either type of regulatory services.

Identification of the Right Service Provider
Development of appropriate regulatory strategies and preparation of suitable regulatory documentation that meets your needs is critical to successful product registrations.

In many instances an outsourcing group manages the initial contacts with contract manufacturers. Once contract manufacturing/development sites are identified, the capability of the contractor to perform specific services is examined, including the experience of personnel involved and determination of the contractor’s regulatory compliance status. Information regarding project goals and submission deadlines are discussed. Identification of regulatory needs, including documentation and data needed to support product registrations, is rarely discussed at this time. This activity should be included in the negotiation phase for contract manufacturing/development.

The capability of regulatory consultants should be determined as part of due diligence by an expert in that field. Expertise requirements become more stringent as the compound moves through the development process. References from several companies may be of valuable assistance in evaluating consultants. Alternatively, your company may establish the reliability and capability of an independent regulatory service provider by having them work at your facility with internal regulatory staff for a period of time prior to assigning them work that may be done outside of your facility.

The following should be considered, as applicable, when selecting a CMC Regulatory consultant.

Confidentiality
A Confidentiality Agreement must be in place with any CMC consultant your company uses. It is important to evaluate their capability to maintain your company’s proprietary information as privileged. Details regarding work in-progress for another client should not be discussed, including the client names, product names, regulatory strategy, submission contents, submission dates, or anticipated approval dates. If your company requests examples of documents previously prepared, those provided for your review should have all confidential information redacted. The manner in which they treat another company’s information is an indicator of how yours will be treated.

The consultant may have information considered to be their company’s proprietary work product, such as Drug Master Files, templates, or guides. When appropriate, it is reasonable for your company to request to examine these documents in their presence with any other client names and product information removed.

Individual Staff Member Capability
Knowledge
Regulatory consultants should demonstrate knowledge of Regulations, Guidances and Regulatory Authority practices. They should be able to convey the registration requirements for the type of drug or readily identify the appropriate applicable regulations and guidance documents that denote them. Any FDA Review Division-specific requirements or region-specific requirements for markets in which your drug will be registered should be acknowledged.

Additionally, they should be able to converse regarding the various registration requirements at different stages of the drug development process. They should also be able to describe in general terms the procedures for investigational, marketing and post-approval applications.

Where contractors are required to prepare a Drug Master File (DMF), they must be knowledgeable of their responsibilities, including providing DMF Authorization letters that meet the Guidance requirements, prompt notification of any proposed changes to the contents of the DMF to allow your company to evaluate the need for regulatory submissions, and annually updating the DMF.

Experience
Consultants must have adequate experience to perform the expected activities. Experience in the pharmaceutical industry, particularly in drug development, is key. The number of years of regulatory submission experience that the service provider has may not be as important as the overall experience of the group and/or the supervisor. An individual’s experience may be evident by examining his CV for the type of companies for which he has worked. For example, an individual who is experienced with only generic companies is unlikely to have CMC experience in registering new molecular entities; however, he should be able to recognize that there are differences in the information necessary for that type of registration and know where to locate the content requirements.

As with new CMC regulatory staff in your company, inexperienced staff at a contractor or regulatory service provider will likely be assigned small early development or post-approval submissions while learning the basics. It is critical for them to work with a mentor with extensive experience during this time. Within approximately two years a new staff member would have gained the basic knowledge to put together a marketing application, respond to deficiency letters and obtain a drug approval with some independence. After approximately five years, a staff member should have extensive experience including independent development of successful regulatory strategies, obtaining dossier approvals for a variety of dosage form types, exposure to various FDA reviewing divisions and international drug registrations, as well as negotiations with regulatory agency reviewers regarding contents of dossiers and/or responses to deficiencies. The individual’s expertise will be dependent on his initiative and the opportunities he has been given by his employers.

Suppliers of regulatory services should be able to give examples of difficult negotiations that they had with a regulatory agency regarding a drug approval. Please note that the description should maintain the confidentiality of any proprietary information for the particular company involved. They should be able to tell you what types of dossiers and number of CMC sections they have prepared for approved products.

Another method of evaluating experience is to ask for redacted documents they have prepared, along with professional references.

Company Capability
Staffing
The company must have appropriate staffing and experience in performing the regulatory advisor, technical writing and publishing functions required to meet your expectations. A small group or even a single individual can perform these functions with the appropriate skill level and an adequate timeline. Alternatively, some activities may be subcontracted to others who have an established business alliance with your provider. Ensure that you have a complete understanding of the capability for these activities by asking how the contract manufacturer and/or regulatory service provider plan to complete the assigned activities.

Another item to consider is the commitment of the contractor to maintaining current knowledge of changes in regulations and guidance documents. Membership in appropriate professional organizations, such as the Regulatory Affairs Professional Society (RAPS) or American Association of Pharmaceutical Scientists (AAPS), acknowledges this responsibility. Regulatory Affairs Certification (RAC) also shows an overall commitment to the regulatory affairs profession. Attendance at conferences, particularly those co-sponsored by regulatory authorities, is mandatory to understanding current agency thinking. Some consultants speak at conferences or are members of professional organization focus groups.

While CMC consultants do not necessarily have to be experts in all of the scientific disciplines for which data are included in dossiers (e.g., organic chemistry, analytical chemistry, pharmaceutical sciences, microbiology), they must have enough of an understanding of each to identify scientific error. They should be able to identify areas where they would need to collaborate with an expert to ensure that any information provided is scientifically correct.

Processes
Any consultant used must have a clearly defined process for preparation, assembly, and review of documentation to be provided to the sponsor. The process should include attainable timelines and adequate scientific and regulatory review by proper company personnel.

An up-to-date manual or guide that defines documentation contents and the data necessary to prepare dossiers signifies careful consideration of the requirements and may act as a checklist to ensure that nothing is overlooked. A regulatory service provider should have a template for dossier preparation that includes all required headings, proposed standard wording, standard data tables and figure locations identified. The templates should be based on submission requirements and consistent with the above referenced content guide. The template should meet the regulatory agency requirements for submission. Additionally, a written style guide for writing dossiers that is based on defined standards (e.g., ACS Style Guide, Technical Writing Style Guide) is useful. These documents may be considered proprietary work products by the service provider, but should be available for your review in their presence.

Additionally, service providers must have the capability of preparing the dossier using your company template and format, if necessary. Your company should be able to insert any “submission-ready” sections into the dossier without any format modification.

Timeliness
Timelines quoted should be achievable based on the availability of the scientific data and the company resources. Proposed review times must be adequate to ensure a complete scientific and regulatory review. A minimum of one week to review small CMC packages and two weeks for review of CMC marketing applications is recommended.

Contingency plans must be in place for potential delays in data availability. Service providers should be able to identify potential delays and describe modifications in the timeline that will have minimal impact on the final milestone date. It is important to check with references regarding their history of on-time delivery.

Collaboration
The most critical item to a successful working relationship between a sponsor and any contractor is open communication. It is vital that any potential issues identified be shared between parties openly.

These collaborations work best when they are looked upon as partnerships rather than as contracts. All participants will benefit from the rapid submission of accurate, scientifically sound, approvable regulatory dossiers. Cooperation and recognition of the valued skills that each participant brings to the process are mandatory to achieve this goal. In collaborations there may be misunderstandings of terminology, deliverables, roles and responsibilities or due dates. Immediate identification and resolution of any issues in a positive manner will keep things running smoothly.

It is particularly important to openly identify any issues that may cause a delay in the overall project. Completion of each milestone requires completion of interdependent activities by all parties – missed delivery dates upstream will impact the capability to meet the final deadline. All parties must be flexible and maintain an understanding of the downstream activities and their durations.

Regulatory Deliverables
It is crucial to agree and clearly document the deliverables that will be provided by the regulatory consultant. An independent CMC regulatory service provider will have experience working with multiple development and manufacturing organizations and multiple sponsors. They will have been exposed to a variety of situations from a regulatory strategy and document preparation standpoint and can identify proven solutions to common issues while maintaining confidentiality. Additionally, they are likely to have had experience in both drug substance and the various drug product type requirements. Like independent service providers, regulatory affairs staff at contract development and manufacturing organizations can determine “best practices” from their experience with multiple sponsors and situations.

The typical regulatory deliverables expected from consultants are regulatory strategy advice and regulatory documentation.

Regulatory Strategy
Identification of appropriate regulatory strategies and potential consequences is key to obtaining product approvals. Experienced CMC service providers can be of valuable assistance in determining an appropriate regulatory strategy for CMC sections. They will be aware of specific FDA Division or other Regulatory Agency requirements that may not be spelled out in the guidance documents.

Once identified, the CMC consultant should be part of the product development team. This will allow early identification of the CMC data that must be obtained to ensure that an approvable dossier is prepared. Additionally, changes to the manufacturing procedures or analytical data anomalies can be evaluated for their impact on product registration. Necessary modifications to the regulatory strategy and opportunities for streamlining data requirements can be determined early in the process rather than later.

The ultimate responsibility for the contents of CMC sections lies with the sponsor. The sponsor is the expert on the development history and attributes of the product. However, input from both the sponsor and the service provider can ensure that the highest quality dossier is prepared with the minimum amount of required data.

Regulatory Documentation
CMC submission deliverables from the contract development and manufacturing providers may be available in two forms: information printouts from their existing systems (“data only”) or submission-ready documentation. Data from the manufacturer may be provided to your company, an independent regulatory service provider, or their own internal regulatory affairs department for dossier preparation.

Identification of the desired documentation deliverable early in the business relationship will prevent difficulties later. Contractors should have a checklist describing the potential deliverables for your examination. Once these deliverables have been identified, the format and contents should be agreed upon. An abbreviated example checklist for drug product documentation is provided in Figure 1.

The documentation responsibilities of the contractor and the dossier sponsor must be clearly defined. A written regulatory strategy for the dossier is important and should include the amount of stability data that will be included in the dossier (number of batches, storage conditions, months stored, packaging configurations, bracketing/matrixing to be used), release data to be included (number of batches, batch sizes), parameters that will be evaluated for analytical method validation, and the information that will be included in the dossier. This strategy may be prepared by the sponsor or jointly with the consultant. Responsibility for submission document preparation, review, formatting, compilation and hypertext linking should be clearly assigned.

Data Only
Documentation systems at contract development/manufacturing organizations are typically created to support manufacturing, product testing, product release and stability operations. Documentation must be in enough detail to allow the company to perform manufacturing and testing procedures. Analytical data are typically stored in laboratory information databases. It is unlikely that the format requirements for regulatory dossiers outlined in guidance documents were taken into consideration when report requirements were identified for internal systems.

Because it is possible that the documentation from their system may not be of a suitable format or level of detail for direct submission to regulatory agencies, sample documents should be inspected to assure that the documents provided will meet expectations. Where the information requires reformatting for submission, responsibility for this activity should be clearly assigned.

It is strongly recommended that any agreements or contracts require that manufacturing and/or development contractors review final CMC dossiers to ensure that they accurately describe the procedures used by their company. This activity should be coordinated through their regulatory affairs or quality department. Additionally, the draft dossier should be reviewed by a regulatory expert.

Submission-Ready Documents
By definition, submission-ready documents should meet all applicable regulations and guidance documents regarding content and format. Additionally, they should support the written regulatory strategy for registration of the product. It is preferred that the format of documents provided by a consultant match that used in the remainder of the dossier (clinical and nonclinical sections). If applicable, all internal CMC section hypertext linking should be performed by the consultant. Both electronic copies (e.g., Word, PDF) and adequately indexed paper copies should be provided.

Preparation of submission-ready documentation by the internal Regulatory Affairs departments of development/ manufacturing contractors may be advantageous because of their daily access to the personnel performing these functions for your project. They will be the most knowledgeable of the facility to ensure that documentation prepared accurately describes their processes while allowing the flexibility needed by their facility. Alternatively, independent CMC regulatory service providers with exposure to multiple manufacturing organization procedures may be responsible for this activity.

Regulatory consultants will not have firsthand knowledge of the development and marketing history for your specific product. For these relationships to be successful it is critical to provide detailed information to the party responsible for dossier preparation. This includes the CMC dossier table of contents, a table of nomenclature to be used (product, generic name, drug substance, chemical intermediates), a lexicon of your company terms including acronyms, style guide (defining header style and numbering, spacing, and fonts), details regarding product development, copies of any previous regulatory filings if applicable, identification of the countries that the product will be registered in, and documentation of any agreements previously made with regulatory agencies.

If possible, the most desirable means of dossier preparation is extraction of analytical data directly from laboratory information systems and databases into the document via a validated computer system. This mechanism reduces the likelihood of transcription errors during document preparation and should be taken into consideration when determining whether to outsource document preparation. However, keying-in data is the standard practice and is perfectly acceptable as long as the review process includes verification of the dossier information vs. the information systems and laboratory notebooks.

The review procedure to be used should be agreed prior to document preparation. The sponsor should determine whether it wishes to review drafts of individual dossier sections as they are prepared or if it wants to perform a single review a compiled draft dossier. The functional areas in both companies that will participate in the reviews should be defined, as should the purpose of each review. If the consultant has an established dossier review procedure, it may be easiest to adhere to its practices. Additionally, a process for resolution of disagreements regarding dossier contents should be established.

Timelines
Identification of achievable target delivery dates should be part of the initial negotiations, including milestone and submission dates. Adequate time must be allowed to ensure that any documents prepared are of high quality, adequately describe the processes, are scientifically sound, and meet regulatory requirements.

Specific target dates should include delivery of documentation and information from the sponsor company to the contract manufacturer and regulatory service provider; delivery of documents from the manufacturer to the regulatory service provider, if applicable; delivery of documents/dossiers from the service provider for review; turnaround times for document preparation and review; and delivery of final documents to the sponsor. Identify what dates are flexible vs. those that absolutely must be met. Additionally, identify any potential consequences and contingency plans for missed deadlines.

Target dates may be missed due to issues encountered during batch manufacture or data availability. Where this occurs, the remaining timeline should be examined to determine whether the original submission date could be met through modifications in the agreed processes.

Dilemmas
There are a number of dilemmas that may arise as a result of working with a regulatory consultant. All can be overcome through constant communication and focus on the ultimate project goal. Some examples of potential issues with recommendations to ensure their appropriate resolution follow:

Region Specific Requirements
Many products are intended for marketing in multiple countries/markets. Region-specific requirements have an impact on product development, registration and specifications. If your product is intended for registration in more than one market, it is important that any requirements be considered as early as possible.

Some countries require that manufacturers submit registration documentation, such as Site Master Files. These documents should be prepared by the contract manufacturer and submitted directly to the applicable regulatory agency when possible. These documents contain information that is likely to be considered to be proprietary by the manufacturer. It is most efficient for the sponsor when the manufacturer takes responsibility for ensuring that these documents are current and adequately describe the organization and activities of the company. However, on-site review of these documents by your staff or an expert CMC service provider should be part of the contract to ensure that they are of the highest quality and will support your dossier approval.

It is preferred for registered specifications to be as similar as possible in all regions. This will allow for the use of a single set of batch analysis and stability tables to be used for a maximum number of registrations. Determination of the stability specifications to be registered will ensure that appropriate results are recorded during development. Please note that European registrations typically have both release and shelf-life specifications.

Proprietary Information
Submissions for sterile products are required to include information regarding validation of the sterilization process. For the U.S., the requirements include a significant amount of information regarding the facility. For biological products it is required that the name of all products manufactured in the facility be included in registrations.

Many manufacturers consider detailed information regarding their buildings, equipment validation and media fill philosophy to be proprietary. Additionally, development/manufacturing contractors will consider the identification of other products manufactured in a multi-product facility as confidential. In these instances, the manufacturer will prefer to submit this non-product-specific information directly to the FDA as a Type V Drug Master File (DMF). Both CBER and CDER will accept submission of proprietary information in this manner.

Reference to a DMF will ensure that the agency will review the most up-to-date information available for the facility. Additionally, it assures that there is consistency with regard to the information submitted for a specific facility in all client dossiers. As a product sponsor, however, it is your responsibility to ensure that the information provided in these Master Files is adequate to support the approval of your product. An on-site review of the most recent DMF submission in which the names of all companies with authorization to reference and all product names are redacted is recommended.

Scope Change
It is not uncommon for the scope of the project and deliverables to be modified during the course of a contract. These may be the result of requests by Regulatory Agencies (e.g., deficiency letters or pre-submission meetings) or additional data obtained (e.g., appearance of new impurities or an increase in the level of impurities during scale-up). Some of these situations may necessitate a change in the originally defined timeline to obtain more information.

It is important that any changes in scope be identified and that the regulatory service provider has clearly documented authorization to proceed with associated activities. Awaiting this authorization from the appropriate party may delay action. All contracts should include an allowance to proceed with activities associated with a scope change, up to a maximum number of hours, prior to receipt of authorization. This will ensure that submission delays are minimized.

Terminology Differences
Each company has its own standard acronyms and terminology. There may be instances where differences between terms used by a sponsor, a development/manufacturing contractor, and a regulatory service provider will cause misunderstandings.

For example, some contract manufacturers may use the term “SOP” to describe information specific to equipment and safety procedures. In this case, SOPs are considered to be confidential, proprietary documents. Conversely, a sponsor may use the term “SOP” to describe the analytical testing procedures used to release product. Imagine the frustration when sponsor requests for copies of SOPs are routinely denied. Such a situation underscores the need for a high level of open communication between sponsors and service providers.

If there is any potential that there is a discrepancy in terminology used, ask for a clear definition or example document.

There are a number of advantages to using a consultant to provide regulatory advice and to prepare/review CMC documentation. Successful collaborations benefit both the sponsor and the service provider. The critical success factors to using a CMC Regulatory Affairs Consultant are identification of the right service provider, clearly defined deliverables, partnering to achieve goals, flexibility and good communication.