Introduction
In calendar year 2018, the FDA approved a record 62 novel drugs, with the Center for Drug Evaluation and Research (CDER) approving 59 and Center for Biologics Evaluation and Research (CBER) approving three cell therapies. The CDER classification breakdown was 40 chemical drugs and 22 biological drugs. It is notable that greater than 50% of the new drugs approved were biologics with many classified as immunotherapies. Industry surveys suggest this trend towards biologics in the pharmaceutical industry will continue with the percentage of biologics in the R&D pipeline between 25 to 50%. Associated with this change is the rapid growth in the field of gene and cell therapy products. Citing the 800 active INDs for cell therapy and gene therapy candidates and the expectation that it will be receiving more than 200 INDs each year by 2020, FDA Commissioner Scott Gottlieb, MD, in January 2019 outlined the FDA initiatives to support timely review and to enable the approval of 10 - 20 such therapies per year by 2025. Gottlieb announced that 50 new clinical reviewers would be added to the CBER staff to address this demand.
What are the challenges ahead to bring cellular therapies to the market? “The key to making gene therapy accessible to patients will be better manufacturing processes”, Peter Marks, CBER Director, told attendees at the Galien Forum in New York City on Oct. 25, 2018, in a panel discussion on gene therapy. “At this point, the FDA has approved one directly-administered and two cell-based gene therapies”, Marks said, “but the Agency has received over 700 Investigational New Drug (IND) applications in the gene therapy field”. As the FDA points out, there is a large gap between R&D, clinical supplies production, and routine commercial production. Other key challenges include controlling costs, maintaining cell viability and potency and preventing potential microbial contamination.
In this article, the author will explore the limitations in technical expertise especially in the field of microbiology within the biotechnology industry.
Biopharmaceutical Approval Road Map
Although the reader is probably familiar with steps taken to obtain regulatory approval, they can be simply summarized as follows:
Discovery: The road to a new medicine begins with selecting a disease target based on an understanding of the underlying mechanisms of the disease and emerging science. Researchers search for a candidate medicine that may have activity on the chosen target associated with the disease.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!
Preclinical Development: Researchers run the potential medicine through a battery of lab and animal tests to understand the activity and safety of the medicine before moving to clinical studies.
Clinical Development: Before moving to studies in humans, the sponsor company submits an Investigational New Drug (IND) Application to the FDA outlining the preclinical findings and clinical plans. Clinical trials are conducted in three phases:
Phase I trials examine safety in a small group of healthy volunteers.
Phase II trials include larger numbers of patient volunteers to assess safety, dosing and effectiveness.
Phase III trials are in a large group of patient volunteers to generate statistically significant information on the efficacy of the medicine.
Is There a Technology Crunch?
When considering the technical resources of the biotechnology industry, it is useful to analyze the companies by size and experience active in this field. The breakdown of the 605 biopharmaceutical product launches from 2007 through 2016 showed the following distribution of launches by commercial category:
- Top 25 pharmaceutical companies (40%)
- Medium size biopharmaceutical companies (30%)
- Emerging biopharmaceutical companies (30%).
Big and middle-sized pharmaceutical companies may have access to capital and staff with broad experience in taking products through discovery to the market place with resources in product development, analytical test development, clinical trial management, regulatory filing, manufacturing process development, and sales and marketing that emerging biotechnology companies usually lack. Also, young people are entering the industry at the same time that the most longterm and knowledgeable personnel are leaving the workforce, leading to challenges in knowledge management. One field with a shortage is classically trained microbiologists.
Does your company have these resource challenges? Emerging companies usually will rely on Contract Development and Manufacturing Organizations (CDMOs) and consultants to provide these essential services in product development, analytical development, clinical supply manufacturing, and regulatory submission. In addition, large and midsized companies may use CDMOs when looking for cost efficiencies or moving into new product domains were they lack current expertise. The author believes that these services must be aggressively managed by a biopharmaceutical company to bring a new drug product from discovery through development to the market. Access to independent microbiological expertise will be an important aspect of this process.
A critical decision is when to use internal sources or an outside contractor (Rosenblatt and Kenyon, 2018). Points to consider when making this decision include:
- What are your current internal manufacturing and testing capabilities?
- How complex and novel are the projects, and do you want to build new manufacturing and testing facilities?
- Do you understand the regulatory approval process?
- Can the clinical supplies manufacturing and testing be accurately forecasted?
- Is the project in early or late-stage development? Should the CDMO be capable of taking the project through to regulatory approval?
What are the biggest surprises a biopharmaceutical company may encounter when working with a CDMO? They include communication issues, working across time zones, unexpected technical challenges, different global regulatory expectations, getting on the CDMO's busy schedule, cost overruns, extended timelines, and Complete Response Letters (CRL) from the FDA delaying approvals, depleting venture capital, and impacting stock prices. Project management and technical experience can anticipate and overcome many of these challenges.
What skill set should you look for in a consulting microbiologist?
They include:
- A thorough knowledge of microbiology as it applies to the pharmaceutical industry.
- An understanding of drug product formulation and product attributes.
- An understanding of unit pharmaceutical manufacturing operations.
- Experience in developing and qualifying compendial microbial tests for novel biopharmaceutical products.
- Familiarity with the drug approval process.
- Ability to adapt to the clients and their CDMO needs.
Chemistry, Manufacturing and Control Sections
The FDA requires all sponsors of investigational new drug products, including investigational gene therapy products, to describe the CMC information for the drug substance (DS) (21 CFR 312.23(a)(7)(IV)(a)) and the drug product (21 CFR 312.23(a)(7)(IV)(b)). FDA may place the Investigational New Drug (IND) application on clinical hold if the IND does not contain sufficient CMC information to assess the risks to subjects in the proposed studies (21 CFR 312.42(b)(1)(IV)). Microbiology information must be included in the Chemistry, Manufacturing and Control (CMC) sections.
The Common Technical Document (CTD) submitted to the FDA contains three modules. They are as follows:
- Module 1: Administrative Documents, Labels, Environmental Analysis and Previously Submitted Information
- Module 2: Summary of quality information
- General Information, Drug Substance and Drug Product, Combination Products, and Product Handling at the Clinical Site
- Module 3: CMC information Drug Substance, Drug Product, and Appendices
Guidance can be found in the following documents:
- 2001 FDA Guidance for Industry M4Q: CTD–Quality
- July 2018 Draft FDA Guidance for Industry - Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
- ICH Guidance Q6A New Chemical Entities (NCE) and Q6B Biological/Biotechnological (Biotech).
The different sections found in an electronic submission may be summarized as follows:
Common Technical Document – Module 3
3.2.S Drug Substance
- 3.2.S.1 General Information
- 3.2.S.2 Manufacture
- 3.2.S.3 Characterization
- 3.2.S.4 Control of Drug Substance
- 3.2.S.5 Reference Standards or Materials
- 3.2.S.6 Container Closure System
- 3.2.S.7 Stability
3.2.P Drug Product
- 3.2.P.1 Drug Product
- 3.2.P.3 Description and Composition of the Drug Product
- 3.2.P.2 Pharmaceutical Development
- 3.2.P.3 Manufacturing
- 3.2.P.4 Control of Excipients
- 3.2.P.5 Control of Drug Product
- 3.2.P.6 Reference Standards
- 3.2.P.7 Stability
Formulation Development
The formulation of biologics will differ depending on whether the product is stored at ambient or refrigeration temperature, lyophilized or frozen. Different platform formulations would be used for cell therapies, large molecule products, and interference RNA. For example, cell therapies will contain cryo-protectants, if frozen; monoclonal antibodies may contain a caking agent, if lyophilized; and iRNA products may be included in liposomes for target cell penetration.
Process Development
Activities related to monoclonal antibody production that involves microbiology include:
- Facility selection
- Master and working cell line maintenance
- Media ingredient selection
- Upstream processing
- Downstream processing
- In-process monitoring
- Virus inactivation validation
- Process equipment and utilities validation
- Equipment cleaning and sterilization validation
- Aseptic filling and lyophilization
Process Validation
Process validation associated with monoclonal antibody production that involves microbiology includes the following:
- Manufacturing process validation
- Virus inactivation validation
- Chromatography column maintenance and cleaning
- Sterilizing filtration validation
- Equipment and packaging component sterilization
- Aseptic filling validation
- Container-closure integrity
- Visual inspection validation
Areas like virus inactivation, sterile filtration and container-closure integrity require specialized expertise and equipment and are best left to contract testing laboratories.
Microbial Contamination Testing
Critical microbiological quality attributes for biologics including cell therapies include sterility, bacterial endotoxins levels, in-process bioburden, absence of mycoplasma and other adventitious agents. Other considerations include container-closure integrity, sterilization process validation, sterile filtration validation, reconstitution and storage requirements, antimicrobial preservative effectiveness (multiuse products only), and stability studies.
Method suitability testing requirements for USP <61> Microbiological Examination of Non-sterile Products: Microbial Enumeration Tests, <63> Mycoplasma Tests, <71> Sterility Tests and <85> Bacterial Endotoxin Tests is described in each chapter.
USP <1223> Validation of alternative microbiological testing methods provides guidance for alternate methods to the compendial tests. A clinical phase-appropriate method validation strategy should be employed with methods fully qualified by phase III clinical supplies manufacture.
Bioburden Screening
USP <61> Microbiological Examination of Non-sterile Products: Microbial Enumeration Tests describes membrane filtration, plate count, and most probable number methods that can be done to quantitatively determine the bioburden of non-sterile drug products. Although 21 CFR 211.110(a)(6) does not specify a test method, it requires that bioburden in-process testing be conducted pursuant to written procedures during the biopharmaceutical drug product manufacturing process. Methods outlined in <61> may be used for bioburden monitoring in biopharmaceuticals.
Pyrogen Screening
The USP <85> Bacterial Endotoxin Tests based on the Limulus Amboecyte Lysate (LAL) test is the gold standard for measuring Lipopolysaccharides (LPS) in biopharmaceutical products. However, non-endotoxins may be responsible for pyrogenic reactions. The older USP <151> Rabbit Pyrogen Test is being replaced with the Ph. Eur. 2.6.30 Monocyte Activation Test (MAT) that detects endotoxin plus cytokine release. MAT is recommended as a development tool prior to first in human studies.
Mycoplasma Screening
USP <63> Mycoplasma Tests describes growth-based mycoplasma screening methods that take at least 28 days of incubation to complete. The Ph. Eur. 2.6.7 guidance states that nucleic acid amplification techniques (NAT) can be used to test for mycoplasma when a complementary test is required or can be used as an alternative. These new generations of rapid test methods are suitable for in-process monitoring, as well as final product testing.
Sterility/Microbial Contamination Screening
Sterility testing may be performed on the drug substance when it cannot be performed on the drug product, as outlined in the final rule: Amendments to Sterility Test Requirements for Biological Products (May 3, 2012; 77 FR 26162 at 26165). Sterility tests for biopharmaceuticals are described in 21 CFR 610.12 Sterility and USP <71> Sterility Tests.
According to the draft cell therapy guidance, the FDA recognizes that the compendial sterility test may not be suitable for all products. Rapid sterility tests may be needed for genetically modified cells administered fresh or with limited hold time between final formulation and patient administration. For genetically modified cells that are administered immediately after manufacturing, in-process sterility testing on samples taken 48 to 72 hours prior to final harvest is recommended for product release. For such products, aside from an in-process sterility test, FDA also recommended that sponsors perform a rapid microbial detection test, such as a Gram stain, on the final formulated product and a sterility test, compliant with 21 CFR 610.12, on the final formulated product. Under this approach, the release criteria for sterility would be based on a negative result of the Gram stain and a no-growth result from the 48 to 72 hour in-process sterility test. Although the results of the sterility culture performed on the final product will not be available for product release, this testing will provide useful data. A negative result will provide assurance that an aseptic technique was maintained. A positive result will provide information for the medical management of the subject and trigger an investigation of the cause of the sterility failure. The sterility culture on the final formulated product should be continued for the full duration (usually 14 days) to obtain the final sterility test result, even after the product has been administered to the patient.
The USP has published a proposed general informational chapter <1071> Rapid sterility/microbial contamination testing of short-life products: a risk-based approach that addresses sterility testing of shortlived products like cell therapies. Currently the industry practice is to use the BacT/Alert Dual-T Microbial Detection System for sterility testing of cell therapy products. Although the sterility of the sample is monitored progressively, the test being growth-based may take up to five days of incubation so that the product may be administered prior to the completion of the test.
How are Emerging Biopharmaceutical Companies Doing with Regulatory Submissions?
Analysis of the FDA reactions to regulatory submissions is possible by reviewing the frequency of Complete Response Letters (CRL). The picture is not pretty. A CRL from the FDA delays a product’s entry to the market by an average of 14 months. Companies that receive the letters take an average of seven months just to respond to them. Imagine how much you could save if you could anticipate the FDA’s concerns and address them before the agency issues the complete response letter? Note: Using older terminology, CRLs were called Deficiency Letters.
Researcher Theresa Allio, Ph.D., analyzed CRLs issued for 51 products approved by the FDA since 2009 and discovered striking underlying patterns: Forty-seven percent of CRLs name deficiencies in CMC requirements. Analysis by Amy Brown in the May 24, 2018 issue of Vantage showed that since the beginning of 2017 only nine of 34 CRL’s issued went to big pharma companies while the remaining 25 (74%) went to smaller companies. The CRL receipt can significantly reduce the capital market value of the smaller companies and delayed regulatory approval.
Conclusions
The decision to use and select a CDMO to move a candidate drug product from discovery through product development, clinical trials, and regulatory submission is critical for an emerging biopharmaceutical company. This article emphasizes that many biopharmaceutical companies lack experience in CDMO selection and do not have resources in the area of microbiology to monitor their activities. The article gives a brief overview of many of the issues, especially in the area of microbiology that companies will encounter going forward with emphasis of the IND/BLA/CMC sections.
References
- Allio, T 2019 FDA Complete Response Letter Analysis: How 51 Companies Turned Failure to Success FDANews
- Brown, A 2018 Are small companies carrying the complete response letter can? Vantage May 18, 2018 Issue
- Rosenblatt, B and Kenyon, D, 2018 In-house versus Outsource: A Decision Making Guide https://patheon.com/resource-library/whitepapers/in-house-versus-outsource-adecision-making-guide/