Designing a biologics manufacturing facility: Early planning for success

This article reviews important steps in the manufacture of biologics. The authors provide planning steps for compliance with current good manufacturing practice (CGMP) to readiness for chemistry, manufacturing, and controls (CMC). They pose important questions manufacturers should address, from facility issues to working with a contract development manufacturing organization. They conclude that trends toward reducing the time to market put considerable stress on all aspects of commercial operations and commercial scale manufacturing process development, making early tactical and strategic planning essential.

Introduction

The drug manufacturing facility environment presents one of the major sources of potential contaminants in the final biologic drug product. It is therefore critical to design facilities with clean-room environmental controls and monitoring that adhere to the highest standards of CGMP quality guidelines. This is particularly true, given that many cell and gene therapy products are not terminally sterilized and/or sterile filtered. Thus, quality tests could be performed with samples not representative of the final drug product and/or are not adequate. In these situations, it is particularly important to manufacture clinical-grade products in an environment deemed suitable for the product type and based on analysis of critical manufacturing and processing steps that could place the product in direct contact with the manufacturing environment.

Strategies for entry into commercial phase

Among the many factors that influence a final product’s quality are the design and location of drug product manufacturing facilities. In the US, unlike in Europe, facilities are not necessarily inspected for compliance with CGMPs during the phase 1 trial but, rather, undergo verification at the time of pre-license inspection. As a result, initial product manufacturing may be driven by practical business needs, such as available space and resources. For example, companies may use a regular research laboratory with a biosafety level 2 biological cabinet, or a room not originally intended as a manufacturing suite for clinical grade products (Stage I). After the product shows promise in early phase clinical studies, some sponsors move their manufacturing to a more controlled and classified (Stage II) environment. Finally, if the phase 3 trial is successful, the third stage of facility upgrade may involve building a new manufacturing facility or contracting with a CGMP-licensed manufacturer.

In the latter stages of clinical development and when preparing for commercial manufacturing, companies often dedicate considerable resources to building a new state-of-the-art manufacturing facility. However, planning for success early on allows for streamlining the process of finding an appropriate manufacturing environment, one that is flexible enough to accommodate further expansion through either scaling up or scaling out, depending on the intended scale of commercial manufacturing. A scale-up strategy may not require a large footprint expansion, but a scaling out of manufacturing, involving replication of manufacturing unit operations will. In view of the inevitable challenges involved in the product development cycle, it is advisable to develop a CGMP facility strategy early on to address manufacturing facility requirements.1

When planning for success, it is important to consider the following questions when designing or selecting a facility for biologic product manufacturing:

• What is the appropriate and flexible environment for manufacturing your product, based on your current state of manufacturing?
• Can you make an earlier move to manufacturing platforms that are more environmentally protected and more amenable to aseptic sampling?
• If not, what are the available manufacturing platforms that are suitable for automation of your process? Are there any existing, functionally closed, platforms that allow you to manufacture products that would require less environmental control and monitoring?
• Can you use isolators as part of your manufacturing?
• What is your plan for commercial manufacturing scaling up or scaling out?
• Will you be using a contract managing organization (CMO) and, if so, do you have an appropriate quality agreement in place to ensure robust manufacture of your product?
• Have you discussed your plan for commercial scale manufacturing with the regulatory agency?

Companies can enlist the services of third-party consultants who provide strategic guidance about an overall manufacturing plan from the phase 1 clinical trial through commercialization for biologic products.

Establishing CMC readiness

Chemistry, manufacturing, and controls (CMC) readiness and adherence to CGMPs are the major hurdles when conducting cell and gene therapy trials. Insufficient CGMP readiness could lead to unnecessary delays and may further complicate and confound interpretation of very costly clinical trial studies. To prevent such problems, manufacturers often ask regulatory authorities for a checklist for CMC readiness ‒ particularly for expedited designations ‒ before entering a pivotal or phase 3 study. Because the US Food and Drug Administration (FDA) does not have a CMC guidance document specifically addressing this, the most important questions to ask in the manufacture of biologics, including cell and gene therapy products, include:

• Has there been a careful review to ensure entering phase 3 trials with an optimized manufacturing process?
• Have major manufacturing changes that may require conducting comparability studies been introduced and, if so, what is the plan to conduct such studies?
• What is the status of the analytic method development? Have assays been qualified, or preferably validated, before initiation of a pivotal trial?
• Are there appropriate potency assays in place for the final drug product?
• Is there knowledge of critical quality attributes, critical process parameters, and key process parameters?
• Has the shelf life of the final drug product been determined by conducting appropriate stability assays that have been qualified/validated?
• Is there a well-defined plan to collect materials and reserve samples for in-process and the final drug product?
• What is the plan of action for conducting process validation to demonstrate the final drug product can be consistently manufactured successfully?
• Are there defined standard operating procedures (SOPs), protocols, and instructions for outlining additional manufacturing, processing, formulation, or thaw/dilution of the final drug product at clinical sites?
• Have the requirements for conducting leachable and extractable studies for materials that are in direct contact with the product been evaluated?
• Has the batch size and manufacturing capacity required for phase 3 trials and commercial manufacture been calculated? Do you anticipate needing to make a change to an existing facility to manufacture the final drug product? Are there plans for automation, scaling out or scaling up after approval for, or before initiation of, the phase 3 study?
• Has there been a final determination on whether the current release specifications are adequate for ensuring safety and potency of your final drug product?
• Has shipping validation for source materials and the final drug product under worst-case scenarios or conditions of transport been conducted?
• Has there been a review of the quality of ancillary materials, reliability, and sustainability of the supply chain? Is there a plan to review your quality agreements and SOPs for material qualification and vendor qualification? Has an identity test for your critical ancillary materials been developed?
• Has the choice of the final container been finalized, and is there a plan for affixing the label on the final drug product?
• Is there a plan for testing the source material, in-process materials, or the final drug product? Do you plan to outsource your testing, or will it be conducted in house?
• Is there a need to develop any in-house standards (physical or performance standards) for assays? Which standards are needed for product development and release testing?
• Has there been an end-of-phase 2 meeting with FDA to assess CMC readiness?

Selecting a CDMO

If you decide to use a contract development manufacturing organization (CDMO), consider whether the organization will perform only manufacturing, or manufacturing and development. It may be more expedient to contract out the development and manufacture of the product, depending on a company’s staffing levels and experience. Either way, an element of technology transfer will be required, and that can be time consuming. The CDMO will need an understanding of the development history of the product’s manufacturing process and group training sessions ‒ for both parties ‒ on topics, such as operations, communication plans, and quality, can foster teamwork and relationship building between the company and the CDMO.2 The company should also provide some level of on-site support at the CDMO to maintain strong communication channels.

A company’s assessment of a potential CDMO should include the following elements:

• Awareness that it (the company) is not the CDMO’s only client. Successful CDMOs can effectively develop mutually beneficial partnerships will their clients.
• The CDMO should have demonstrated expertise in manufacturing similar product types to those the company will want manufactured.
• Consideration of facility and equipment availability at the desired manufacturing capacity.
• An audit of the potential CDMO to examine quality systems, GMP compliance, and compliance history.

Once a company has selected a CDMO, manufacturing and quality agreements should be executed to delineate project aspects and responsibilities of each party.

Early planning: Commercial scale manufacturing points to consider

It is in the sponsor’s best interest to consider planning for commercial launch early on during clinical development, given the current trend among global regulatory agencies to offer accelerated approval pathways for advanced therapies.

Even under an accelerated approval pathway, regulatory reviewers and inspectors will still expect to see an adequate display of manufacturing consistency, control, and quality oversight before granting approval for commercial manufacture.

At this point in the product lifecycle, answers to the questions presented in the preceding section of this article should be incorporated into appropriate policy documents, production procedures, and product specifications. These policies should address the seven systems of GMP compliance (see below) that will be assessed in pre-license or preapproval inspections. It is worth noting that, when the FDA’s form 356h3 is completed and submitted, there is a checkbox to indicate the applicant is ready to be inspected.

The seven systems are listed here, with noteworthy items for inclusion into a company’s commercial manufacturing strategy:4

• Quality

• Finalization of critical quality attributes
• Adequate and detailed investigations and deviation management
• Evaluation of CAPAs for effectiveness
• Batch release – are any rework or reprocessing activities allowed? If so, was this assessed in process validation studies?
• Procedures finalized for annual product review, complaints, biological product deviation reports, and recalls
• Ongoing assessment of quality metrics – systems that show visibility of commercial control

• Production
  • Establishment of detailed production process instructions, along with manufacturing batch records that document and assess in-process controls and significant process steps
  • Finalization of qualification and validation activities supporting product commercial manufacturing process, including process validation with appropriate holds and time limits, aseptic simulations, and cleaning validation
• Facilities and equipment
  • Adequate environmental monitoring during production and after production in International Organization for Standardization (ISO) 5 and ISO 7 classified areas
  • Environmental sampling locations are near areas of critical operations
  • Cleaning procedures for equipment and facilities are detailed to ensure consistent execution by operators
• Laboratory controls
  • Adequate system for tracking and managing flow of samples
  • Suitability of testing methods determined under actual conditions of use
• Materials
  • Routine acceptance and rejection of components that do not meet specifications for identity, strength, quality, and purity
  • Adequate segregation and labeling of material storage areas
  • Periodic verification testing of certificate of analysis results for components
• Packaging and labeling
  • Establishment of visual inspection limits with appropriate defect rates and acceptable quality limit stringency
  • Adequate verification and validation of shipping conditions
  • Security and reconciliation of issued labels and templates
• Donor eligibility (if applicable)
  • Establish and maintain procedures for all steps you perform in testing, screening, and determining donor eligibility to comply with requirements of part 1271, subpart C of the Code of Federal Regulations (donor eligibility).5
  • Appropriate identification and records of eligibility accompany the collected unit throughout manufacture and distribution
  • Responsible person to determine and document eligibility
  • Screening for relevant and current communicable diseases and agents of concern

Inspections performed as part of the biologics license application (BLA) submission review are designed to assess the above systems in operation to ensure consistent manufacture of a safe product. In the current coronavirus pandemic environment, the inspection may be performed either on site or virtually, or may consist of a records review, based on whether the applicant has a favorable inspection history.

Mechanisms that companies can use to prepare for this inspection consist of pre-BLA meetings and Type C facilities meetings6 with FDA. These meetings allow the applicant to provide information to the regulatory agency for feedback regarding elements of product and facility controls. They also serve to give the agency an opportunity to weigh in on the acceptability of policies before the review cycle and pre-license inspection, thus avoiding potential review issues and delays. Major issues arising during the inspection or BLA submission review can jeopardize first-cycle approval or add delays to the action due date for the submission.

Companies can also subject their product dossier and facility to a gap analysis and mock inspection by consulting firms using former FDA regulators to perform these activities. By doing that, program areas with gaps, or potential objectional conditions, can be identified and corrected before meetings with the FDA and in advance of submitting the dossier.

Conclusions

As advanced therapies continue to be developed and demonstrate benefit to patients, the expectation for faster time-to-market will increase. The combination of multiple clinical study phases into a single trial will also potentially accelerate the time between the investigational new drug application and the BLA submission of a therapeutic product. Reducing the time to market will place considerable stress on all aspects of commercial operations and commercial scale manufacturing process development, making early tactical and strategic planning essential for success.

Abbreviations

BLA, biologics license application; CDMO, contract development manufacturing organization; CGMP, current good manufacturing practice; CMC, chemistry, manufacturing, and controls; CMO, contract manufacturing organization; SOP, standard operating procedure.

References

1. Heidaran M. Establishing manufacturing controls: A hurdle for the cell and gene therapy industry. https://www.raps.org/news-and-articles/news-articles/2019/4/establishing-manufacturing-controls-a-hurdle-for. Regulatory Focus. Posted 25 April 2019. Accessed 19 July 2020.
2. Khoury T, Gara G. Best practices for CDMO evaluation, selection, and management. Projectfarma website. http://projectfarma.com/2020/07/08/best-practices-for-cdmo-evaluation-selection-and-management/. 8 July 2020. Accessed 19 July 2020.  
3. Food and Drug Administration. FDA forms. https://www.fda.gov/about-fda/reports-manuals-forms/forms. Last updated 10 July 2020. Accessed 19 July 2020.
4. Allen E. FDA perspective on GMPs for cell & gene therapies. Presentation at ISPE Biopharmaceutical Manufacturing Virtual Conference; 1-2 June 2020.
5. Food and Drug Administration. Code of Federal Regulations Title 21, vol. 8 ‒ Food and Drugs; Part 1271 ‒ Human cells, tissues, and cellular and tissue-based products; Subpart c ‒ Donor eligibility. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271&showFR=1&subpartNode=21:8.0.1.5.60.3. Revised 1 April 2019. Accessed 19 July 2020.
6. Food and Drug Administration. Formal meetings between the FDA and sponsors or applicants of PDUFA products guidance for industry. https://www.fda.gov/media/109951/download. December 2017. Accessed 19 July 2020.

About the authors

Mo Heidaran, PhD, is vice president, technical at Parexel International. Before joining Parexel, he served at the FDA for about 9 years in the Office of Tissues and Advanced Therapies and the Office of Compliance and Product Quality as product reviewer, CGMP expert, acting team leader, and branch chief and facility reviewer/inspector. He has a PhD in biochemistry from the University of South Carolina. He can be contacted at Mo.Heidaran@parexel.com.

R. Heath Coats, MS, is a principal consultant with Parexel international. Before joining Parexel, he served as a reviewer and inspector for 7 seven in the FDA’s Division of Manufacturing and Product Quality in the Office of Compliance and Biologics Quality. Before his tenure at FDA, Heath directed the validation program at Lonza Walkersville for 9 years, which included supporting Lonza’s cell therapy contract manufacturing. Heath has a master of science degree in biomedical science from Hood College, Maryland. He can be contacted at Heath.Coats@parexel.com.

Steve Winitsky, MD, is a vice president of technical at Parexel International. Before joining Parexel, he served at the FDA for 11 years in the Office of Tissues and Advanced Therapies in the Center for Biologics Evaluation and Research as clinical reviewer, then later team lead, and most recently acting clinical branch chief for general medicine. He has an MD from the University of Miami School of Medicine. He can be contacted at Steve.Winitsky@parexel.com.

Citation Heidaran M A, Coats R H, Winitsky S. Designing a biologics manufacturing facility: Early planning for success. Regulatory Focus. July 2020. Regulatory Affairs Professionals Society