Cgmp For Phase 2 Investigational Drugs
Eustacio Gadit
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Because a phase 1 clinical trial initially introduces an investigational new drug into human subjects, appropriate CGMP help ensure subject safety. This guidance applies, as part of CGMP, quality control (QC) principles to the manufacture of phase 1 investigational drugs (i.e., interpreting and implementing CGMP consistent with good scientific methodology), which foster CGMP activities that are more appropriate for phase 1 clinical trials, improve the quality of phase 1 investigational drugs, and facilitate the initiation of investigational clinical trials in humans while continuing to protect trial subjects.
Everyone in the pharmaceutical manufacturing industry understands or has at least heard of current Good Manufacturing Practices (cGMP). The requirements of the cGMPs are prescribed in Title 21 of the Code of Federal Regulations parts 210 and 211 (better known as 21 CFR part 210 and 211). But there is a unique situation in which the requirements of 21 CFR 211 in the manufacture of a drug are exempt. That is for the manufacture of Phase 1 investigational drugs.
Often, small pharmaceutical and biotechnology companies have their hopes riding on the success of one, maybe two, drugs. And as is also often the case, these companies have limited funds to advance the drugs into trials. Understanding the ramifications of this exemption and how to implement the desired manufacturing practices can save a company much time and money.
21 CFR 312.21(a) describes phase 1 investigational trials. Phase 1 clinical trials are typically small in size (20 to 80 patients), the patients are healthy, and the goal of the trial is to determine the metabolism and pharmacologic actions in humans, tolerability (i.e., side effects), and if possible, determine evidence of effectiveness and thus its potential for further development. Additionally, Phase 1 trials are closely monitored by trained health care professionals.
What the FDA is suggesting is not to spend time and money on meeting all the requirements of 21 CFR part 211, but to spend effort, time, and money toward ensuring the equipment is functioning correctly (through a commissioning program), and develop clear and specific procedures and batch records that describe and record the manufacturing process.
In summary, the FDA has allowed for an exemption to the cGMPs of 21 CFR part 211 for the manufacture of Phase 1 investigational drugs. The FDA recommends a subset of those requirements, based on a risk-based approach that relies on procedures, facilities, and equipment that provide for the safe manufacture of the drug. The FDA realizes that Phase 1 drugs are in their infancy and are investigational; the FDA wants the companies to spend their time and effort on ensuring a safe and well-documented manufacturing process, and it does not want to hinder the development of drugs due to manufacturing regulations.
Daniel Carpenito has over 31 years of experience in process engineering, commissioning, project management, validation, and quality assurance. His broad client experience ranges from small research sites to large biotech and pharmaceutical facilities to contract manufacturers.
Each phase of clinical research has its own unique goals and challenges. While clinical research is generally divided into four phases, two additional stages are sometimes part of the process:
These are conducted before clinical research begins and typically involve in vitro and in vivo studies to collect data pertaining to the efficacy, toxicity, and pharmacokinetics of a drug, vaccine, or diagnostic assay. Only when the results of such studies are favorable will the development of a drug move forward.
In most cases, volunteers are healthy, but in certain circumstances, patients who have terminal cancer, HIV, or other conditions are recruited instead, as treatments for such diseases may make healthy subjects ill.
After a range of doses is settled upon during the first phase of clinical research, the second phase studies the drug on a larger group of subjects to determine its safety and efficacy. Phase 2 is often divided into two sub-phases; the first is a pilot study focused on effectiveness and biological activity, while the second determines the optimal dose.
Next, we move to Phase 3 of clinical research, which weighs the overall effectiveness of the drug and its value in clinical practice compared to the current dominant treatment for a disease or condition. There are many test subjects, making this phase one of the most expensive, difficult, and time-consuming.
The FDA recommends that manufacturers conduct a comprehensive evaluation of the manufacturing setting to identify any potential hazards when it comes to the equipment and manufacturing environments. Before and during the manufacturing process, actions are taken to eliminate or minimize hazards to preserve the integrity of Phase 1 investigational drugs.
Using disposable equipment and process aids, prepackaged materials, closed process equipment, and contract or shared cGMP manufacturing and testing facilities can all help ensure that a pharmaceutical company complies with cGMP guidelines for phase 1 clinical manufacturing.
Personnel involved in the manufacturing process should have adequate education, experience, and training to carry out their roles, including knowledge of QC principles and the statutory requirements of cGMP.
Diligent record-keeping is vital during Phase 1 manufacturing. Records should be kept to detail the materials, equipment, procedures followed, and problems encountered during manufacturing; they should also keep track of changes in procedures and processes for subsequent batches and outline the microbiological controls implemented for sterile-processed Phase 1 investigational drugs.
Laboratory Controls
Laboratory controls include testing materials, in-process materials, packaging, and drug products, along with stability studies of Phase 1 investigational drugs once manufactured. Tests should be performed under controlled conditions, follow written procedures, and results should be recorded. Representative samples from each batch should be retained and stored for at least two years after a clinical trial is terminated or an IND application is withdrawn.
We have the knowledge, experience, and facilities to support you through all stages of drug development, including Phase 1 clinical manufacturing. Contact us today to learn more about our capabilities and how we can help get your drug to market sooner.
There is additional FDA guidance for Phase I clinical trials using cGMP for investigational drugs. According to 21 CFR 210.2(c), the cGMP regulations formally apply for drugs used in Phase II/III studies.
There are many benefits to implementing cGMP as early as possible in drug development. Beyond protecting participant safety, cGMP provides a foundation for a sound quality management system (QMS). Adopting a QMS early allows processes to gradually integrate, which benefits research staff.
Additionally, early adoption ensures tighter controls, builds organization-wide quality, and minimizes noncompliance risks. For organizations moving toward commercialization, this helps assure a successful pre-approval inspection.
However, cGMP requirements can be difficult to understand. In an effort to clarify, FDA adopted the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use:
Complying with cGMP throughout the drug development process helps ensure quality investigational products. This also helps protect clinical trial participant safety and reduces variability due to poor quality. Even with outsourced manufacturing processing, sponsors are still responsible for meeting cGMP requirements.
Investigational drugs must follow current good manufacturing practices (CGMPs) when they reach phase 1 clinical trials, as this stage represents their first introduction to human subjects.2,4 However, there is still room for error: the Institute for Safe Medication Practices (ISMP) found potential for errors in naming practices, drug labels, packaging, product appearance, and expiration dating among study sponsors.3 As well, phase 1 investigational drugs are still new chemicals, meaning there is often little information on potential toxicity.5
As with all hazardous drugs, the US CGMPs also state that the use of closed-system transfer devices, ensuring that the investigational drug is not exposed to the environment during processing, can alleviate the need for stricter room classification for air quality.4 Studies show that the use of closed-system transfer devices may help reduce hazardous drug contamination.7 The European CGMPs mention that special attention should be paid to ensure safe handling of investigational drugs to avoid cross contamination, identifying the importance of establishing a sufficient quality control system.14
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