The Lifecycle from Drug Development Through Approval Processes

Robert Dream- Managing Director, HDR Company, LLC

The average lifecycle of drug development from discovery to approval is about 10 to 12 years. The total time varies depending on the previous knowledge and experience gained by similarity to an approved and licensed drug product that is on the market, and the type of regulatory approval process that the drug product goes through (Figure 1). Only about 8 to 10% of drug products from the preclinical phase become FDA approved drug product. Ultimately, the goal is to have safe and effective drugs available to the prospective patient.

The steps of the drug approval process from discovery and development to post market safety monitoring is summarized in the following steps (Figure 2):

Step 1: Discovery and Development

Step 2: Preclinical Research

Step 3: Clinical Research

Step 4: FDA Drug Review and licensing

Step 5: FDA Post-Market Drug Safety Monitoring

Note: The treatment IND [21 CFR 312.34 and 312.35] is a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments.

Step 1: Discovery and Development

Research for a new drug begins in the laboratory as a two-tier process, first is discovery and then followed by development, as follows;

Discovery

Typically, researchers discover new drugs through;

• New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease
• Many tests of molecular compounds to find possible beneficial effects against any of a large number of diseases
• Existing treatments that have unanticipated effects
• New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material

At this stage in the process, thousands of compounds may be potential candidates for development as a medical treatment. After early testing, however, only a small number of compounds look promising and call for further study.

Development

Once researchers identify a promising compound for development, they conduct experiments to gather information on:

• How it is absorbed, distributed, metabolized, and excreted
• Its potential benefits and mechanisms of action
• The best dosage
• The best way to give the drug (such as by mouth or injection)
• Side effects or adverse events that can often be referred to as toxicity
• How it affects different groups of people (such as by gender, race, or ethnicity)
• How it interacts with other drugs and treatments
• Its effectiveness as compared with similar drugs

Step 2: Preclinical Research

Before testing a drug in humans, researchers must find out whether it has the potential to cause serious harm, also called toxicity. The two types of preclinical research are:

• In Vitro
• In Vivo

FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for preclinical laboratory studies. The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies. These regulations set the minimum basic requirements for:

• study conduct
• personnel
• facilities
• equipment
• written protocols
• operating procedures
• study reports
• system of quality to assure each study safety of FDA-regulated product

Usually, preclinical studies are not very large. However, these studies must provide detailed information on dosing and toxicity levels. After preclinical testing, researchers review their findings and decide whether the drug should be tested in humans.

Step 3: Clinical Research Phase Studies

Drugs are tested on people to make sure they are safe and effective.

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or trials, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins:

1. Designing Clinical Trials
2. Clinical Research Phase Studies
3. The Investigational New Drug Process
4. Asking for FDA Assistance
5. FDA IND Review Team
6. Approval

Designing Clinical Trials

Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called protocol, that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide:

• Who qualifies to participate (selection criteria)
• How many people will be part of the study
• How long the study will last
• Whether there will be a control group and other ways to limit research bias
• How the drug will be given to patients and at what dosage
• What assessments will be conducted, when, and what data will be collected
• How the data will be reviewed and analyzed

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies. Known as the Clinical Research Phase Studies:

Clinical Research Phase Studies

Phase 1

Study Participants: 20 to 100 healthy volunteers or people with the disease or condition.

Length of Study: Several months

Purpose: Safety and dosage

Approximately 70% of drugs move to the next phase

Phase 2

Study Participants: Up to several hundred people with the disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy and side effects

Approximately 33% of drugs move to the next phase

Phase 3

Study Participants: 300 to 3,000 volunteers who have the disease or condition

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Approximately 25-30% of drugs move to the next phase

Phase 4

Phase 4 trials are carried out once the drug has been approved by FDA during Post-Market Safety Monitoring;

Study Participants: Several thousand volunteers who have the disease

Purpose: Safety and efficacy

The Investigational New Drug Process

Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.

In the IND application, developers must include:

• Animal study data and toxicity (side effects that cause great harm) data
• Manufacturing information
• Clinical protocols (study plans) for studies to be conducted
• Data from any prior human research
• Information about the investigator

Asking for FDA Assistance

Drug developers are free to ask for help from FDA at any point in the drug development process, including:

• Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research
• After Phase 2, to obtain guidance on the design of large Phase 3 studies
• Any time during the process, to obtain an assessment of the IND application

Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet federal standards, FDA allows wide latitude in clinical trial design.

FDA IND Review Team

The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities.

• Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor.
• Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete.
• Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data.
• Pharmacologist: Reviews preclinical studies.
• Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes. Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules.
• Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, and the presence of impurities.
• Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes.

Approval

The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials. FDA responds to IND applications in one of two ways:

• Approval to begin clinical trials
• Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including:

» Participants are exposed to unreasonable or significant risk

» Investigators are not qualified

» Materials for the volunteer participants are misleading

» The IND application does not include enough information about the trial’s risks

A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In most cases, if FDA is satisfied that the trial meets federal standards, the applicant is allowed to proceed with the proposed study.

The developer is responsible for informing the review team about new protocols, as well as serious side effects seen during the trial. This information ensures that the team can monitor the trials carefully for signs of any problems. After the trial ends, researchers must submit study reports.

This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials.

Step 4: FDA Review and Licensing

FDA review teams thoroughly examine all of the submitted data related to the drug and make a decision to approve or not to approve the drug product.

If a drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file an application to market the drug. The FDA review team thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve the drug product.

New Drug Application

A New Drug Application (NDA) tells the full story of a drug. Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied.

A drug developer must include everything about a drug in the application. From preclinical data to Phase 3 trial data, in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include:

• Proposed labeling
• Safety updates
• Drug abuse information
• Patent information
• Any data from studies that may have been conducted outside the United States
• Institutional review board compliance information
• Directions for use

FDA Review

Once FDA receives an NDA, the review team decides if it is complete. If it is not complete, the review team can refuse to file the NDA. If it is complete, the review team has six to ten months to make a decision on whether to approve the drug. The process includes the following:

• Each member of the review team conducts a full review of his or her section of the application. For example, the medical officer and the statistician review clinical data, while a pharmacologist reviews the data from animal studies. Within each technical discipline represented on the team, there is also a supervisory review.
• FDA inspectors travel to clinical study sites to conduct a routine inspection. The Agency looks for evidence of fabrication, manipulation, or withholding of data.
• The project manager assembles all individual reviews and other documents, such as the inspection report, into an “action package.” This document becomes the record for FDA review. The review team issues a recommendation, and a senior FDA official makes a decision.

FDA Approval

In cases where FDA determines that a drug has been shown to be safe and effective for its intended use, it is then necessary to work with the applicant to develop and refine prescribing information. This is referred to as “labeling.” Labeling accurately and objectively describes the basis for approval and how best to use the drug.

Often, though, remaining issues need to be resolved before the drug can be approved for marketing. Sometimes FDA requires the developer to address questions based on existing data. In other cases, FDA requires additional studies. At this point, the developer can decide whether or not to continue further development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal.

FDA Advisory Committees

Often, the NDA contains sufficient data for FDA to determine the safety and effectiveness of a drug. Sometimes, questions arise that require additional consideration. In these cases, FDA may organize a meeting of one of its Advisory Committees to get independent, expert advice and to permit the public to make comments. These Advisory Committees include a Patient Representative that provides input from the patient perspective.

Step 5: FDA Post-Market Safety Monitoring

FDA monitors all drug and device safety once products are available for use by the public.

Even though clinical trials provide important information on a drug’s efficacy and safety, it is impossible to have complete information about the safety of a drug at the time of approval. Despite the rigorous steps in the process of drug development, limitations exist. Therefore, the true picture of a product’s safety actually evolves over months and even years that make up a product’s lifetime in the marketplace. FDA reviews reports of problems with prescription and over-the-counter drugs, and can decide to add cautions to the dosage or usage information, as well as other measures for more serious issues.

Supplemental Applications

Developers must file a supplemental application if they wish to make any significant changes from the original NDA. Generally, any changes in formulation, labeling, or dosage strength must be approved by FDA before they can be made.

INDs for Marketed Drugs

If sponsors want to further develop an approved drug for a new use, dosage strength, new form, or different form (such as an injectable or oral liquid, as opposed to tablet form), or if they want to conduct other clinical research or a post-market safety study, they would do so under an IND.

Manufacturer Inspections

FDA officials conduct routine inspections of drug manufacturing facilities across the United States, and abroad if approved products are manufactured overseas. Manufacturers may be informed of inspections in advance, or the inspections may be unannounced. Inspections may be routine or caused by a particular problem or concern. The purpose of these inspections is to make sure that developers are following good manufacturer practice. FDA can shut down a facility if minimum standards are not met.

Drug Advertising

FDA regulates prescription drug advertisements and promotional labeling. By law, a developer is prohibited from advertising unapproved uses of their product.

All advertisements, such as product claims or reminder ads, cannot be false or misleading. They must contain truthful information about a drug’s effectiveness, side effects, and prescribing information. These advertisements can be found in medical journals, newspapers, and magazines, and on the Internet, television, or radio.

Promotional labeling differs from drug advertisements in the way it is distributed. Pharmaceutical companies give out brochures or other promotional materials to physicians or consumers. The drug’s prescribing information must accompany promotional labeling.

Reporting Problems

FDA has several programs that allow manufacturers, health professionals, and consumers to report problems associated with approved drugs.

• MedWatch is a gateway for reporting problems with medical products (drugs and devices) and learning about new safety information. You can subscribe to regular MedWatch safety alerts.
• Medical Product Safety Network (MedSun) monitors the safety and effectiveness of medical devices. FDA recruits 350 healthcare providers throughout the United States to report any medical device problems that result in serious injury or death. Each month, FDA publishes the MedSun newsletter. The newsletter gives consumers important information about medical device safety.

Active Surveillance

Under the Sentinel Initiative, FDA is developing a new national system to more quickly spot possible safety issues. The system will use very large existing electronic health databases like electronic health records systems, administrative and insurance claims databases, and registries to keep an eye on the safety of approved medical products in real time. This tool will add to, but not replace, FDA’s existing postmarket safety assessment tools.

Considerations for the CTD Modules

Organization of the common technical document for the registration of Bio-pharmaceuticals for human use, Figure 3.

Module 1: Administrative Information and Prescribing Information

This module should contain documents specific to each region.¹⁰ The content and format of this module can be sspecified by the relevant regulatory authorities;

• 1.1 - Table of contents of the submission including module 1
• 1.2 - Documents specific to each region (application forms, prescribing information)

» 1.2.1 - Forms

» 1.2.2 - Cover Letter

» 1.2.3 - Administrative information

» 1.2.4 - References

» 1.2.5 - Application status

» 1.2.6 - Meetings

» 1.2.7 - Fast track

» 1.2.8 - Special Protocol assessment request

» 1.2.9 - Pediatric administration

» 1.2.10 - Dispute resolution

» 1.2.11 - Information amendment: information not covered under module 2 to 5

» 1.2.12 - Other correspondence

» 1.2.13 - Annual Report

» 1.2.14 - Labeling

» 1.2.15 - Promotional material (promotional-material-audience-type)

» 1.2.16 - Risk management plan

» 1.2.17 - Postmarketing studies

Module 2: Summaries

Module 2 should begin with a general introduction to the pharmaceutical, including its pharmacologic class, mode of action, and proposed clinical use. Module 2 should contain 7 sections in the following order;

• 2.1 - Common Technical Document Table of Contents
• 2.2 - Introduction to Summaries
• 2.3 - Quality Overall Summary (QOS) – M4Q⁶
• 2.4 - Nonclinical Overview – M4S⁷
• 2.5 - Clinical Overview – M4E⁵
• 2.6 - Nonclinical Written and Tabulated Summaries – M4S⁷
• 2.7 - Clinical Summary – M4E5 The organization of these summaries is described in guidelines for M4Q, M4S, and M4E.^5-7

Module 3: Quality

Information on Quality should be presented in the structured format described in guideline M4Q.⁶

• 3.1 - Table of Content of Module 3
• 3.2 - Body of Data

» 3.2.S - Drug substance [name, manufacturer]

» 3.2.P - Drug Product [name, dosage form, manufacturer]

» 3.2.A - Appendices

» 3.2.R - regional information

• 3.3 - Literature References

Module 4: Nonclinical Study Reports

The nonclinical study reports should be presented in the order described in guideline M4S.⁷

• 4.1 - Table of Contents of Module 4
• 4.2 - Study Reports

» 4.2.1 - Pharmacology

» 4.2.2 - Pharmacokinetics

» 4.2.3 - Toxicology

• 4.3 - Literature References 

Appendices (A, B, C)

Module 5: Clinical Study Reports

The human study reports and related information should be presented in the order described in guideline M4E;⁵

• 5.1 - Table of Contents of Module 5
• 5.2 - Tabular listing of all clinical studies
• 5.3 - Clinical study reports
• 5.4 - Literature references

Proof of Concept Versus Prototype

Proof of concept (PoC): Is a theoretical demonstration of a product/ process/concept. It determines whether an idea could be turned into a reality. Test whether the idea is viable and explore the idea’s potential to be developed or built. Verify that the idea will function as envisioned. Identify the potential technical issues that might interfere with success. Address how the proposed product or service will support organizational goals, objectives or other business requirements as a secondary goal. Not intended to explore market demand for the idea, nor is it intended to determine the best production process.

Prototype: Is a very early draft of a product/process/concept. Meant to turn a PoC idea into a slimmed-down version of the end product that could be tested and evaluated for usability, functionality and design. Not expected to have all the features and functions of a market ready product, nor is it expected to contain all the usability or aesthetics of a final product. Give stakeholders, project managers, executives, and potential investors a draft of what the final product might be. Allows makers to determine how best to develop the product when it moves into full production for a final, market entry item.

Drug Master File

A drug master file (DMF)¹¹ is a confidential, detailed document submitted by the drug substance manufacturers to the U.S. Food and Drug Administration (FDA). A DMF contains the chemistry, manufacturing, and controls of a drug component. A drug master file is filed when two or more firms work in partnership on developing or manufacturing a drug product. The DMF filing allows a firm to protect its intellectual property from its partner while complying with regulatory requirements for disclosure of processing details. The DMF contains factual and complete information on a drug product’s chemistry, manufacture, stability, purity, impurity profile, packaging, and the cGMP status of any human drug product. The pharmaceutical industry is one of the most regulated industries; no drug would be marketed without the teams of medical researchers and other specialists who worked to make sure it receives regulatory authority’s approval. There is no legal or regulatory requirement to file a DMF.

The drug master file is provided in 21 CFR 314.20. DMF is a set of documents submitted to the FDA by a biopharmaceutical manufacturer. The drug master file may also provide information which may be confidential for the company, may be required by regulatory authorities for complete understanding of their product, facility, and the processes, systems, and equipment used for various processes such as manufacturing and quality assurance, or storage and distribution.

The drug master file is submitted by a biopharmaceutical manufacturer to support various applications.

• Investigational new drug application (INDA)
• New drug application (NDA)
• Biologicals License Application (BLA)
• Abbreviated new drug application (ANDA)
• Export application
• Another DMF or amendments and supplements to any of these application The DMF is not a substitute for an INDA, NDA, BLA, ANDA, or export application.

A DMF in support of application for approval of a new drug should provide information about;

• Drug substance.
• Intermediates.
• Drug products.
• Excipients.
• Packaging materials.
• Flavors.
• Essence.
• Colorants.
• Substance used to make them
• Stability data of drug products

The FDA never approves or disapproves a DMF. The DMF staff (FDA) only checks whether it is administratively completed or not. FDA reviews DMF in context with an INDA, NDA, BLA, ANDA, or export application. These applications may reference the context of DMF wherever it is applicable. The DMF is submitted in two copies to FDA, one copy must be retained by the person or holder who is submitting DMF.

Types of DMFs

Four types of DMF’s are covered by 314.20, as illustrated below;

Type I DMF: Subject of information provided in the DMF.

Note: Type I DMFs were discontinued in 2000 but the numbering of the DMF types has not changed, FDA’s approach to the terminology for types of master files used for products subject to approval under the PHS Act has generally tracked its approach to the types of DMFs (e.g.; Type II, Type III) used for products regulated under the FD&C Act.

Type II DMF: Drug substance, drug substance intermediate, and material used in their preparation, or drug product

Note: Although FDA’s approach to the use of master files in BLAs under the PHS Act largely parallels its approach to the use of DMFs in applications under the FD&C Act, there is a significant difference: a BLA holder is generally expected to have knowledge of and control over the manufacturing process for the biological product for which it has a license. For biological products in BLAs under the PHS Act, FDA has, as a scientific matter, generally not permitted applicants to incorporate information about drug substance, drug substance intermediate, or drug product by reference to a master file; rather, FDA generally expects such information to be submitted directly to the BLA.

Type III DMF: Packaging material

Type IV DMF: Excipient, colorant, flavor, essence, or material used in their preparation

Type V DMF: FDA-accepted reference information

Process Characterization

Process characterization is the study of a process to identify its key variables and determine how those variables can be controlled. It is an essential tool for any organization that wants to ensure quality and efficiency in their manufacturing processes. Process characterization can be used to assess both existing and new processes. When characterizing a new process, it is important to consider all of the potential variables that could affect product quality, including, both physical variables (e.g.; time, temperature, mixing speed) and process variables (e.g.: ingredient concentration, pH impurities). Once all of the potential variables are identified experiments could be conducted (DoE; Design of Experiments) to determine which parameter/variable actually have an impact on the process. Screening designed experiments test multiple variables at high and low settings (LDL, lower decision limit and UDL, upper decision limit) to determine which are critical to quality, Figure 5. The outcome of the DoE designed experiments evaluate the interaction between the critical variables to identify the optimal setting of each critical variable. The flow chart, Figure 4 illustrates the experimental design process.

Process characterization helps achieve greater production efficiency and quality

Process characterization identifies the variables with greatest impact on the process. Once these variables are identified, a company can establish production and process controls to ensure the process is consistently performed in a manner that optimizes its results. Optimized processes lead to greater efficiency, higher yields, reduced production downtime, and overall improved product quality.

Process characterization requires planning and time, and requires skilled personnel with strong technical acumen. To the casual observer, process characterization can slow the product development lifecycle, and increase startup costs before the product has an opportunity to generate income. However, these costs are an up-front investment cost, as important as, or even more important than initial commercialization costs. The reason is process characterization prevents avoidable expenses related to product failures, recalls, backorders, and customer abandonment. As such, process characterization is an essential tool for any organization that wants to ensure quality and efficiency in their manufacturing processes.

Process characterization can help achieve greater efficiency and quality during production by providing valuable insights into manufacturing. By understanding how the process works and what variables impact it, you can make necessary changes to improve efficiency and quality.

Process characterization is a critical step in developing any new manufacturing process. It allows you to identify and control the key variables that will impact the process.

What to consider before implementing Process Characterization?

Before starting process characterization, it is important to consider the following:

• What are the objectives?
• Which processes need to be characterized?
• What resources (people, equipment, facilities, investment cost) are required?
• What type of data do you need to collect?

By answering these questions, you can develop a clear plan for how to proceed with process characterization. This will help ensure that the process is conducted effectively and efficiently!

Key Benefits of Process Characterization

If you want to ensure efficient and effective manufacturing, then you need to characterize your process! There are many benefits to conducting process characterization studies, including the following:

• Process Expertise: Characterization builds organizational expertise by identifying key variables and determining how those variables can be controlled.
• Improved Quality: By understanding the key variables that impact the process, one can more easily control them to ensure product quality.
• Greater efficiency: Process characterization can identify areas where the process is inefficient and suggest ways to improve it.
• Cost savings: By improving process efficiency, you can reduce production costs.
• Reduced risk: Process characterization can help identify potential risks associated with the process and take steps to mitigate them.
• Enhanced Productivity: Process characterization will maximize product yield and minimize production costs, adding to the bottom line.

Pre-Approval Inspection Compliance Program 7346.832

Pre-Approval Inspection Compliance Program 7346.832, Rev. 4, eff. 5/12/2010.

The Food, Drug, and Cosmetic Act provides that FDA may approve an NDA or an ANDA only if the methods used in, and the facilities and controls used for, the manufacture, processing, packing, and testing of the drug are found adequate to ensure and preserve its identity, strength, quality, and purity.

Site Evaluation Before approval, FDA evaluates the establishments by on-site inspections and/or by establishment file review when the firm is named in the Chemistry, Manufacturing, and Controls (CMC) section of a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Biologic License Application (BLA).

Which sites generally trigger a facility evaluation for a pre-approval inspection? Facility evaluations are conducted for;

• Finished dosage manufacturers
• API (Drug Substance) manufacturers
• Finished dosage and API (Drug Substance) testing sites
• Primary packaging and labeling sites
• For animal derived APIs, the facility that performs the crude extraction

When does FDA perform PAIs?Use risk-based Priority Inspection Criteria to make the decision based on the following risks;

• Facility Risk

» cGMP issues relevant to application product

» Recent FARs relevant to application product

» Recent recalls relevant to application product

» Numerous applications filed at once

• Product Risk

» New molecular entity

» First application filed by applicant

» First ANDA filed for an approved drug

» RLD (Reference Listed Drug) has complaints, ADEs (Adverse Drug Experience), stability issues

» Patient population or for serious condition

» Breakthrough therapy, shortage situation

• Process Risk

» Narrow therapeutic range (95%-105%)

» API (Drug Substance) derivation is high risk (derived from animal tissue)

» PAT, NIR, QbD » Development data is incomplete

» Batch records non-specific

» Complicated process

» Substantially different process than previously covered at facility

The Pre-Approval Inspection Team

If an inspection is determined to be needed FDA will send a team of individuals to conduct the pre-approval inspection. The team may include: Investigators, Other Specialists – Chemistry Expert – Microbiology Expert – Process/Facility Expert – Formulation Expert.

A pre-approval inspection (PAI) is performed to contribute to FDA’s assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete. PAI is product specific;

• Limited or no commercial manufacturing
• More focus on development data
• More emphasis on authenticity of data and application commitments
• Process validation commonly not completed
• Application actions are administrative; typical enforcement used for marketed products do not apply
• Trend toward more experts involved in the inspection

Pre-Approval Inspection Coverage

Objective 1: Readiness for Commercial Manufacturing. Determine whether the establishment(s) has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.

Objective 2: Conformance to Application. Verify that the formulation, manufacturing or processing methods, and analytical (or examination) methods are consistent with descriptions contained in the CMC section of the application for the biobatch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and the API(s).

Objective 3: Data Integrity Audit. Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the CMC section of the application. Verify that all relevant data (e.g., stability, biobatch data) were submitted in the CMC section such that CDER/CBER product reviewers can rely on the submitted data as complete and accurate.

Pre-Approval Inspection Outcomes

The inspection is one part of the approval process. The lead investigator will make a recommendation at the conclusion of the inspection:

• Recommend Approval:

» Indicates that the inspection found no significant issues

» Response to observations is important

» Recommend Withholding of Approval;

• Investigators observed that the site is not GMP compliant, information in CMC is not consistent with site records, or information submitted is not accurate and complete

» Response to observations is critical

Clinical Development Versus Process Development Timelines

A comprehensive plan and the right regulatory and therapeutic expertise can significantly accelerate the development timeline and increase the likelihood of marketing success, especially for small biotech and bio-pharma companies working with limited time and resources. This overview provides critical planning activities and milestones in the drug development process, along with important regulatory considerations at each stage. Those products that are being marketed for the first time contain a new molecular entity or new active moiety. Also investigate how FDA regulatory programs may affect this process.

Biopharma process development comprises the activities that help create a series of steps to produce a biomolecule – e.g.; monoclonal antibody (mAb), recombinant protein, viral vector, or other product that comes from a biological origin.

Bioprocess development is often divided into upstream process development and downstream process development. Those activities must be combined with the right analytics, so you can accurately measure what identified as the product’s critical quality attributes (CQAs) as develop and refine the processes.

Process development activities will vary by type of biomolecule, as well as the stage of the drug development process are in – preclinical, early clinical (Phase 1-Phase 2), or late clinical (Phase 3-Phase 4). Regulatory requirements will guide many of these activities.

At early stages of drug development, will develop a process that is ‘good enough’ to meet the needs of that stage. However, it’s important to keep the end goal in mind. Ultimately, you will need a process that translates to a manufacturing environment, one that is easy to scale up throughout clinical trials and to the market. By the time it reaches Phase III in the drug development process, ‘good enough’ is not sufficient. Instead, you will switch your focus to making sure you have a robust upstream or downstream process that delivers a high yield and high productivity. Also, your process must be cost-effective and reproducible.

The summary of clinical development vs process development timeline is illustrated in Figure 7.

References

1. ICH M2 EWG, Electronic Transmission of Individual Case Safety Reports Message Specification, (ICH ICSR DTD Version 2.1), Final Version 2.3 Document Revision February 1, 2001.
2. The eCTD Backbone Files Specification for Module 1, FDA, Nov. 1, 2012.
3. Guidance for Industry, M2, eCTD Specification, Questions & Answers, and Change Requests, FDA, March 2005.
4. Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use, M4, Current Step 4 version, dated June 15, 2016.
5. Revision of M4E Guideline on Enhancing the Format and Structure of Benefit-Risk Information in ICH Efficacy - M4E(R2), Current Step 4 version, dated 15 June 2016.
6. The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality – M4Q(R1), Quality Overall Summary of MODULE 2, MODULE 3: Quality, Current Step 4 version, dated 12 September 2002.
7. The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Safety – M4S(R2), Nonclinical Overview and Nonclinical Summaries of MODULE 2, Organization of MODULE 4, Current Step 4 version, dated 20 December 2002.
8. Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications, Guidance for Industry, FDA, February 2020, Electronic Submissions, Revision 7.
9. 21 CFR Part 312 (up to date as of 12/23/2022), Investigational New Drug Application.
10. Addendum 2 to the eCTD Backbone Files Specification for Module 1, Version 2.3, 04/01/2015.
11. Title 21--Food and Drug, Chapter I, Food and Drug Administration, Department of Health and Human Services, Subchapter D - Drugs for Human Use, Sec. 314.420 Drug Master File, Nov 29, 2022.
12. Food and Drug Administration Compliance Program 7346.832, Implementation Date: 10/17/2022.
13. Center for Biologics Evaluation and Research, SOPP 8410: Determining when Pre-License/ Pre-Approval Inspections are Necessary Version: 4 Effective Date: January 6, 2020.

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