What happens when a clinical investigator is also the person with an idea for a new drug? He or she envisions how and why it works, and possibly has experimented with it to help understand it better, and to confirm the idea is on the right track. Then the researcher begins to think about his or her role as initiator and as the principal investigator (PI), and the roles of study coordinators, project managers, and patient recruiters who will be needed to manage the clinical study phases of the Investigational New Drug (IND)1 process for approval through the U.S. Food and Drug Administration (FDA).
What about the physical drug itself? This article includes background information about the physical drug path that may be useful to investigator-initiated research teams. Unlike company-sponsored efforts, the source of the physical drug may not be clear. It could be a current drug or combinations of current drugs, with a new use, dosage type, or dosing structure. It may be a chemical that is not currently used as a drug, like a vitamin or food derivative. Or perhaps it’s a new chemical entity, reflecting a revision to a precursor chemical, or an entirely new structure.
There are two major aspects for the drug’s path forward. One is the clinical research path to provide evidence that the drug works and is not harmful to patients. The other path relates to the physical/ chemical drug itself, as without it, nothing can be done. When the drug investigator is also the sponsor, he or she assumes 100% of the sponsor responsibilities that typically are managed by a sponsoring pharmaceutical company. The physical drug path, and the chemistry, manufacturing, and controls (CMCs) needed to produce a drug product for clinical trials and subsequent commercial distribution are discussed.
The active pharmaceutical ingredient (API) must be obtained and converted into a finished drug for use in clinical testing. APIs may be obtained through manufacturers and suppliers if currently available, or through the chemical manufacturing process on a small scale. There are many forms the finished drug can take, such as tablets or capsules, liquids, creams or ointments, sterile injectable, skin or buccal patch, or an inhaled product.
The physical drug may seem to be the easiest issue to deal with in the overall investigational process, especially when compared to the clinical research involved. In reality, producing a drug with the right physical properties to meet metabolic conditions requires specialized chemistry knowledge, equipment, and supplies. Without a proper development plan, product quality and variation can pose risk to patients and the project.
Small-scale manufacturing in a lab or pharmacy produces limited quantities of drug. The limited scale or imprecise equipment can result in product and batch-to-batch variation. This can affect drug quality, leading to negative impacts on patients, clinical responses, and consistency of outcomes. In addition to drug quality concerns, the veracity of the drug quality can be questioned if the testing is not properly qualified and documented.2 This can result in patients being put at risk, and delays of the project and FDA reviews and approvals. Corrective action often requires repeating production and clinical efforts.
When it comes to the drug product development and the clinical efforts, the legal responsibilities for all aspects of the requirements belong to the sponsor. These requirements are established first and foremost to protect the public and patients’ rights. Some necessary and useful drugs have never made it to the market, or did not stay on the market, because these requirements were not properly met.
Getting the Drug Made
There are four major aspects of getting a drug made:
- Manufacturing of the API
- Manufacturing of the drug product(s)
- Packaging of the final drug product
- Testing of the API and drug product ingredients, processes, final form, and the stability of the API and finished drug product
(Packaging of the API is an aspect of manufacturing the API, but does not have the criticality of packaging the drug product for clinical trials. The manufacturing of the drug product will include the manufacturing of placebo products needed for the clinical trials.)
Pursuance of the physical drug isn’t just linked to the clinical plans. Many activities must precede having the dosage ready for first usage in patients. Depending on the history of the drug (new chemical entity, current drug, etc.) some pre-IND stage activities require the API and drug be put through pharmacology and toxicity studies in animal models. Other activities are required to develop a final form for use, and to provide the assurance that all of the drugs used for the clinical trials are equivalent and meet defined specifications. These assurances must be met before the drug product is administered to humans.
Facilities, Equipment, Personnel
The facilities used to manufacture the API and drug product should be registered for those purposes with the FDA. (The FDA has specific registration requirements for APIs, drug products, testing labs, and other supporting facilities in the drug development and commercial stages.) Some early-stage activities may be allowed in nonregistered facilities, but that action can lead to delays, significant efforts to justify activities, or rejection of the activities.
Depending on the phase of clinical trials, the facility should be qualified and validated. Qualification provides documented and testing evidence regarding the environment (heating, ventilation, air conditioning, cleaning, microbial levels) and the utility supports (electricity, steam, hot water, process water and water quality). Additional current Good Manufacturing Practice (cGMP) quality systems3 are required, such as procedures, calibration, documentation, etc. cGMP requirements are extensive, and not typically practiced in a pharmacy or lab setting.
In addition to the FDA, other regulatory agencies may have oversight within the facility, dependent on the activities performed. These can include the Drug Enforcement Administration4 for scheduled drugs, class materials, and specific equipment reports; the Environmental Protection Agency5 for environmental exposures of the chemicals; and the Occupational Safety and Health Administration6 as relates to occupational exposure of workers to activities, chemicals, and solvents. Most companies have their own internal structures to ensure compliance with regulations and laws, but liability can still extend to use of their services without assuring their controls.
Like the facility, any equipment used in the manufacturing, packaging, and testing of the drug product needs to be qualified and validated. Qualification assures that it has been installed properly and is operating as intended. Validation is testing of the equipment for specific purposes, and is different from operational qualification checks. In addition, there are specific validation requirements based on processes and test methods (discussed below). The quality system controls must extend to the equipment.
The personnel performing manufacturing, packaging, and testing; support personnel (like maintenance, quality); and supervision/management must all be qualified and trained for their assigned tasks. This includes training on the quality systems used to control the facility and equipment, and in the cGMP regulations.
The chemical synthesis of APIs can be simple to complex and influences the manufacturing process and costs. It can also influence its use in the drug product and the stability of the API and drug product. The primary factors are the ingredients, the process and controls, and the specifications.
Availability and quality influence the selection of ingredients. Some may be readily available but their quality questionable. The long-term implications of availability and quality need to be thought through. Lower quality ingredients can result in unacceptable levels of impurities or influence the ability to purify the final drug substance. Some ingredients impact the intended final product’s reaction rates or conditions, and can result in expensive processes. Early-stage use may be low and seem to be inconsequential, but scaling up to clinical or commercial levels could be problematic and expensive.
Process and Controls
If the chemical process can be varied, then the effects of any variations on the long-term research need to be assessed. Variations could cause issues with costs of ingredients or impact the physical structure of the final form. This structure can have a major impact on drug product formulation and processes. Once the primary process is established, then the specific process controls and purification need to be finalized. These efforts support the development reports, which then impact the process validation. (Process validation refers to validating the specific ingredients, equipment, processes, and controls to produce a known compound of specific and defined attributes.)
The final API will need to be physically and chemically characterized. This information is used to develop the API specification. That specification includes the product attributes that are critical to its use (as a drug product), and includes limits of manufacturing and degradation impurities. Part of this characterization includes stability testing of the API. That testing assesses the impacts of temperature, moisture, and time on the API, and includes assessing for protective aspects of packaging. Accelerated stability testing and forced degradation are also performed using acids, bases, and light exposures.
Each of the drug products (dosage forms, strengths) undergo efforts similar to the API—ingredients (formula), processes, and controls. Unlike chemical synthesis, most drug product processes change the physical characteristics of the API and the ingredients added. These physical characteristics can have a direct impact on the properties, stability, and pharmacokinetics of the finished product.
Validation ensures the equivalence of drug products from batch to batch, or before and after any process changes. Control of product variation is critical to ensure the equivalence of clinical trial materials and their potential effect on clinical outcomes. Making multiple small batches in a pharmacy or lab can result in significant unit variability that directly impacts clinical outcome statistics. To set the proper batch size, consider the long-term demand for the drug, through multiple clinical efforts, laboratory testing, and stability assessments (plus sufficient retained samples as required for all studies).
The drug product specification is developed to ensure the proper level of API is present and the physical state (dosage form, color, condition, etc.) of the drug product is appropriate for use. It also ensures that active ingredient is stable, based on levels of degradation impurities. The API can degrade due to the environmental conditions it is exposed to and its interaction with other ingredients. The physical state of the drug can change due to these exposures. Stability is influenced by environmental exposure and the protective nature of packaging.
Packaging is critical to providing protective conditions for the contents of a package. In addition to the packaging container and its closure, there are other critical aspects of packaging at the clinical (and then commercial) stages.
- Labeling identifies the contents of the package and includes specific directions for the dispenser or user of the product contained. The controls for creating and printing this labeling, and attaching it to the packaged product, assure the medications given match the clinical protocol design criteria.
- Blinding is a specific type of labeling of product or placebo to ensure there are no biases in the clinical trial effort (by the staff or the patient).
- Traceability of packaging and supporting records and documentation (including distribution) provides assurance of the identity of any given drug product and package as being of a specific API, manufacturing, packaging and labeling batch, and handling of that batch post production (including use by the laboratory).
Testing provides the evidence of outcomes from the physical drug and clinical trials. The veracity of the drug, the clinical protocol, and the tests all must be assured. Evidence is achieved through testing. Lack of evidence, no matter how minor, can result in patient risk and questioning of the drug quality, clinical efforts, and the statistical outcome. Typically the only way to overcome such a condition is to repeat the efforts. Repeating any of the manufacturing, testing, and/or associated clinical trials will have a significant impact on the project’s cost and result in a delay of product approvals.
The facility and equipment qualification and validation, and the personnel requirements that apply to manufacturing and packaging, also apply to laboratories. A minor exercise like calibration checks of a laboratory balance can have major implications on test results. (Example: If calibration failure results in the incorrect amount of standard being weighed, and that standard is used for critical stability or clinical trial testing, the resulting data may not appropriately reflect (+ or -) what actually occurred.)
Drug standards must be established and characterized. These standards (typically from a batch of the API that has been further purified) are used to qualify subsequent standards or directly for testing. Some standard lots can be used for years, so their initial and ongoing quality and storage, and re-verification, can impact laboratory outcomes for those years.
Just as manufacturing processes are validated for outcomes, analytical test methods must be validated. Analytical methods taken from the United States Pharmacopeia-National Formulary are to be qualified for their use in the lab. The requirements for method validation are extensive and specific. They include linearity, accuracy, precision, system suitability, detection and quantitation limits, and robustness. They serve not only to assess the methodology, but also the equipment, the laboratory, and the personnel involved.
Analytical methods are needed for testing the specification properties and attributes of the API and drug product. Examples of these chemical and physical tests include:
- Assays looking for trouble spots, including impurities (via manufacturing processes, residual solvents, and degradation)
- Methods for identification of the API and drug product against a recognized or qualified standard
- Explorations of the API’s and drug product’s physical properties such as structural elucidation and dissolution
- Examinations of biological properties (at the microscopic level, etc.)
These methods may apply to the final forms of the API and drug product, or may be used to test intermediate forms for validation or process controls, or after packaging as applied to stability and shipping integrity. (Similar method validation efforts apply to the specific analysis of patient biological fluid samples from clinical trials.)
The thought and background research efforts that lead to major projects resulting in new drugs or drug forms represent exciting and impactful steps on the road to improvements in healthcare. The clinical trial efforts of the various research team members are seen as a continuation of the earliest stages of the research. The development of the physical drug is critical to the clinical research efforts in pursuit of drug approvals. The physical drug efforts are part of the stepwise reporting of CMC activity to the FDA, through the IND and various clinical phases of drug research and development.
How the physical drug is produced can impact the patients, costs, timing of supply, and acceptance of the drug product. The quality of the activity can influence the potency, precision, and accuracy of the drug and its use in the clinical environment. The compliance of the activities to registration, reporting, statutory, and guidance requirements will influence their acceptance by the regulatory authorities and serve for long-term evidence of performance of the drug product to meet those requirements.
The legal responsibility and liability for assurance that drug requirements are met is equivalent to that taken for the clinical trial efforts. Attempts to save time or money on the physical product or its requirements are shortsighted and can put at risk all the good work completed or planned. Proper support and direction can help ensure all outcomes move toward supporting the product’s approval by the regulatory agencies. These efforts support the overall value and intellectual property of the drug. Knowledge of the physical drug product activities helps the sponsor-investigator, and all of the various supporting managers and coordinators, to ensure that drug variability is not the source of clinical variation. This ensures clinical research reflects clinical outcomes and not product issues.
- FDA website for New Drug Development and approval process: www.fda.gov/Drugs/BIODevelopmentApprovalProcess/default.htm
- Guidance for Industry Q9 Quality Risk Management: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073511.pdf
- Guidance for Industry Q10 Pharmaceutical Quality System: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073517.pdf
Philip K. Burns (firstname.lastname@example.org) provides compliance, regulatory, and operations consulting to pharmaceutical and medical device clients, and is a founder and partner of CROConsulting.