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The authors explore and define common industry approaches and practices when applying GMPs in early development.
The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically driven standards and regulations for pharmaceutical and biotechnology products worldwide. In previous issues of Pharmaceutical Technology, papers written by the IQ Consortium’s GMPs in Early Development Working Group described the desire and rationale for more clear and consolidated recommendations for GMPs in early development (Phase I through Phase IIa) (1-5). A summary of the key discussions related to analytical method validation, stability, and manufacturing was presented in Part VI of this series (6). In part seven of this series, the IQ Consortium presents a summary of key specification discussions that were part of the IQ Consortium’s recent workshop, Best Practices and Applications of GMPs for Small-Molecule Drugs in Early Development, which was based on these earlier papers.
The workshop was held on Feb. 4–5, 2014, in Washington D.C. Attendees included more than 70 analytical; formulation development; quality assurance; and chemistry, manufacturing, and controls (CMC) regulatory scientists, representing more than 20 companies and FDA.
The presentations consisted of industry representatives summarizing the previously published IQ Consortium papers (2-5) as well as FDA representatives who spoke on the same topics. The breakout sessions were designed to stimulate deeper discussion on specific topics and sharing of best practices across the industry. The presentation materials and key messages from general presentation sessions and the related breakout sessions are available on the IQ Consortium website (www.iqconsortium.org). Although there were no specific agreements reached, there were constructive discussions throughout the workshop.
During the presentations and breakout sessions, approaches and their rationale for specifications in early development garnered significant interest. It was widely agreed that a risk-based, staged approach to specifications that focused on patient safety was appropriate in early development when process, formulation, and method changes are expected. Later in development, a growing process and product understanding allows specifications that take into account manufacturing consistency and clinical relevance to make International Conference on Harmonization (ICH) Q6A more applicable. It was noted that, while there is no current guidance at the Center for Drug Evaluation and Research (CDER) on specifications in early development, the general concept that specifications evolve during development is well accepted, and that the regulations at 21 Code of Federal Regulations (CFR) (312.23(a)(7)(i) emphasize the graded nature of manufacturing and controls information (7). Attendees at the workshop discussed the importance of having appropriate specifications with reasonable flexibility that can help meet the goals of ensuring patient safety and collecting information to determine which attributes of drug substance and drug product are important for safety and efficacy.
A primary topic of interest during the presentations and associated breakout session discussions included justification of impurity specifications using simplified control strategies for formulations like powder in bottle (PiB) or powder in capsule (PiC), and clearly communicating control strategies in the investigational new drug (IND) application. This emphasis within the submission may provide clarity when additional tests not listed on the specifications are an important part of the control strategy or provide product understanding.
In justifying the impurity specification, the drug substance (DS) used in IND-enabling toxicological studies is crucial for aiding specifications development in early phase studies by defining the acceptable levels of impurities for clinical DS. The majority of companies in the discussion use a common drug substance batch for both preclinical safety studies and the first clinical batch, noting the advantage of ensuring all impurities are qualified and the utility of setting appropriate Phase 1 specifications.
With respect to the identification threshold, the practice of most participants was to assign/propose structures to impurities when present at 0.1-0.2% using liquid chromatography coupled with mass spectrometry (LC/MS) and exact mass determinations. Confirmation of structure is performed later in development through synthesis or isolation, followed by characterization of an impurity standard. The limit appeared consistent with FDA current guidance and practice: “Procedures to evaluate impurities to support an NDA (e.g., recommended identification levels) may not be practical at this point in drug development. Suitable limits should be established based on manufacturing experience, stability data, and safety considerations” (8).
Establishing a higher qualification threshold generated much more discussion. It is a multidisciplinary topic that requires consideration from a preclinical safety perspective as well as CMC. During the discussion, several companies outlined their approach as being conservative and consistent with ICH guidelines with a concern that any questions of the qualification of impurities could delay clinical trials. Several companies do have standards for defining when qualification thresholds may exceed 0.15%, but not always as high as 0.5%. Companies that do routinely use qualification limits greater than 0.15% in early phase studies do so considering many factors in the use of the drug product. Factors considered may include consultation with colleagues in toxicology, proposed structure of impurities and knowledge of synthetic route, ICH S9 exception, duration of study, single dose study or short duration, and dose. Sections of the final M7 guidance of special relevance to early development include Sections 5.3 and 8.6 (Considerations for Clinical Development), Section 9.1 (Documentation for Clinical Trial Applications), Appendix 1 (Scope Scenarios), and the recommendations for implementation timelines (final page) (9).
Most companies presently control chiral impurities with the same limit as any other related substance. Consideration of the likelihood of the presence of a particular diastereomer or enantiomer is a legitimate justification for not including them in specifications, especially in multi-chiral center DS. When there are multiple chiral centers, alternate approaches may be considered, such as analysis of the drug substance by optical rotation or by controlling chiral purity upstream in intermediates or starting materials.
When discussing impurities and the control strategy in the IND, it was recommended to include discussion in both the impurities and the justification of specifications sections, with a priority to discuss impurities not qualified and not present in the preclinical batch. Generally speaking, proactively providing justification for specifications (or lack thereof) in regulatory filings has been successful and is encouraged.
Attendees also discussed the limited knowledge of which quality attributes affect DP performance in early development and how the industry approaches this when setting specifications. With a focus on ensuring that accurate and reproducible dosing can be achieved in the clinic and that patient safety is not compromised, characterization data are acquired, reported, and monitored to gain an understanding of the drug product in the context of characterizing chemical, processing, and packaging sensitivities in early development.
Simple DP formulations such as PiB or PiC were favored in early phase development by most of the companies present. These formulations allow the advantage of offering a simplified control strategy based on DS knowledge. For impurities control, drug substance release and stability data are often used, in combination with short in-use stability studies (e.g., for holding of reconstituted PiB). In some cases, testing is discontinued for uniformity of dosage units (content uniformity or mass uniformity) and assay if manufacturing batch records for filled weights are collected as an in-process test. Microbial limits testing on oral solid dosage forms is also often not performed in early phase development, with justifications of knowledge of the manufacturing environment, product and process knowledge, and demonstration of low water activity.
A majority of companies perform disintegration testing at release as an alternative to dissolution testing with PiBs, PiCs, and formulation platforms designed to rapidly disintegrate. Those that do perform dissolution in early development do so generally to inform formulation development and solubility testing for poorly soluble DS. For these compounds, dissolution testing may be introduced as a release test for the intended final formulation. The regulatory agency perspective on this approach is that it can be justified for highly soluble compounds, but for moderately to poorly soluble compounds, dissolution testing should still be considered. For PiB formulations, when DS undergoes almost instantaneous dissolution in the chosen vehicle upon shaking (within a few seconds) at room temperature, no investigation or recording of dissolution time is necessary in early development. Similarly for PiC formulations of a highly soluble drug substance, disintegration within 15 minutes per United States Pharmacopeia (USP) General Chapter <701> is generally sufficient to ensure that the capsules rupture to allow the release of the drug for absorption, but dissolution testing may not be necessary. This is also generally appropriate for capsules with a highly soluble drug substance formulated with excipients in Phases I and IIa. For less-soluble drug substances, dissolution testing is recommended with at least “report results” criteria in the specification.
“Report results” (RR) or “For Information Only” (FIO) acceptance criteria are often used for tests such as moisture, x-ray powder diffraction (XRPD), and dissolution as part of the release and/or stability testing. Companies, however, perform this type of testing in different manners. They are often performed as in-process controls with tighter limits than the final specification, or as part of information gathering in early development to inform future control strategies in Phase III and marketing applications. Some companies report these data on certificates of analysis and some mention them in the specification justification of a regulatory submission. Others, however, do not include the information in the filing. It was noted that from a reviewer’s perspective, providing information on all tests performed on a DS or DP would provide greater clarity that the attributes are being studied. Summarizing the control strategy in the IND helps provide clarity about the information being routinely gathered.
There is often a significant amount of information that is gathered about the DS and DP using interntal tests that may not be part of the early development regulatory filing. Examples discussed included dissolution studies under non-sink conditions or in multistage media. Philosophies on what and how much of this information to share in filings varied significantly between attendees. Additional test results that provide information on the safety of the material to be used in early development studies are helpful, while results gathered to provide process consistency information do not add significant value to the filing and may not be necessary to include. During the discussion sessions, some participants were concerned that disclosing these additional tests in a filing might commit them to continued testing, even after it has been shown not to provide value. However, several suggested sharing detailed results may not be needed. Instead, simply providing a summary of what additional tests are being used or what attributes are being monitored for process understanding with no commitment to continue may provide clarity to regulatory reviewers.
The authors thank Linda Ng, Stephen Miller, Mahesh Ramanadham, and Ramesh Sood from FDA for their participation and contributions to the workshop and this summary.
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2. D. Chambers et al., Pharm. Technol. 36 (7) 76-84 (2012).
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5. M. Coutant et al., Pharm. Technol. 36 (10) 86-94 (2012).
6. C. Li et al., Pharm. Technol. 38 (11) 48-50 (2014).
7. 21 CFR 312.23(a)(7)(ii)
8. FDA, Guidance for Industry, INDs for Phase 2 and Phase 3 Studies, Chemistry, Manufacturing, and Controls Information (CDER, May 2003).
9. ICH, M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, June 23, 2014.
Q. Chan Li is senior principal scientist at Boehringer Ingelheim; Jackson D. Pellett is a scientist at Genentech; Michael Szulc is a principal scientist at Biogen-Idec; Mark D. Trone is a director at Alkermes; and Kirby Wong-Moon is a principal scientist at Amgen.
Vol. 38, Issue 12
Citation: When referring to this article, please cite it as C. Li et al., "Part VII: GMPs for Small-Molecule Drugs in Early Development-Workshop Summary," Pharmaceutical Technology 38 (12) 2014.