Q. Chan Li

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 

 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 (

). 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 

) (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 

 (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.

 36 (6) 54-58 (2012).
	2. D. Chambers et al., 

 36 (7) 76-84 (2012).
	3. R. Creekmore et al., 

 36 (8) 56-61 (2012).
	4. B. Acken et al., 

 36 (9) 64-70 (2012).
	5. M. Coutant et al., 

 36 (10) 86-94 (2012).
	6. C. Li et al., 

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
	Pages: 38-40
	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," 

Articles

The authors explore and define common industry approaches and practices when applying GMPs in early development.

Part VII GMPs for Small Molecule Drugs in Early Development Workshop Summary

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 

, 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). In this paper, the IQ Consortium presents a summary of key analytical method validation, stability, and manufacturing 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.

	Workshop 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 (6).  Although there were no specific agreements reached, there were constructive discussions throughout the workshop.

	A summary of the key discussions related to analytical method validation, stability, and manufacturing is outlined in the following sections.  A summary of the key discussions related to specifications in early development will be the subject of a future article.

	Analytical method validation in early development workshop output

	Workshop discussions regarding method validation in early development focused on validation parameters for compound-specific methods and general methods, as well as industry terminology.  There was general agreement with phase-appropriate method validations as outlined in the position paper (2) as long as sound scientific judgment is used. The group recognized that method validation is not a singular event performed to satisfy a regulatory requirement. Rather, validation should be thought of as an ongoing exercise that evolves every time the method is used. Although there was agreement that evaluating robustness and intermediate precision did not have to be part of the method validation process in early development, consensus on some other validation elements was not reached. Specifically, there was some discussion that, even though it is routinely evaluated by most companies, linearity may not be a critical parameter to evaluate in early development since the criteria are almost always easily met. In addition, there was discussion regarding whether the use of system suitability in lieu of a separate method-validation process could ensure that the method performance (e.g., linearity, precision, specificity, sensitivity, etc.) was suitable for the intended use.

	There was considerable discussion during the presentations and breakout session regarding the terminology used to describe validation activities. Specifically, the apparent interchangeable use of “validation” and “qualification” was discussed.  The lack of consistency in the terminology has led to unnecessary debate and confusion across the industry and in communications with regulatory authorities. Harmonization of clarifying terminology such as Stage 1 validation, Stage 2 validation, or fit-for-purpose (FFP) validation might provide greater clarification on the stage of validation.

	Approaches for validating general methods, such as gas chromatography (GC) residual solvent, heavy metal, and compendial methods varied within the industry. In most cases, compendial methods are evaluated to determine suitability of use, but are not validated.  However, some companies performed validation of FFP general methods (e.g., GC residual solvents) for each drug substance (DS) and/or drug product (DP) sample matrix as compound specific methods.  In contrast, other companies validated these methods for each individual analyte (e.g., solvent or metal), but did not perform additional validation for every DS and/or DP matrix.

	Drug product manufacturing in early development workshop output

	Results from the 2011 survey on early development manufacturing practices (3) highlight two areas that could benefit from open discussion: batch documentation and change-control systems.  There was consensus at the workshop that batch records and change-control systems need to be designed to accommodate manufacturing flexibility in early development. Feedback from participants indicated that many companies have implemented approaches that allow this flexibility.  The following are some examples of these approaches as well as discussion notes:

Only providing process parameter ranges in batch records when sufficient process knowledge has been accumulated.

 This approach reduces the number of process “deviations” that need to be addressed during or after a campaign.  While health authorities would like to see some targets/ranges specified, they are mainly interested in knowing that the manufacturer has adequate controls and knows what steps must be taken to assure high quality product for the clinic.  It is important, however, to provide enough instruction in the batch record such that actual set points or values observed during processing are recorded and deviations from expected performance are clear.

Several companies are moving away from having the quality unit preapprove batch records. 

In the 2011 survey, 100% of the 10 companies that responded indicated that their quality units preapprove batch records.  Since the survey, one company has removed the requirement for packaging operations.  Another company performs daily, concurrent batch record review with the quality unit during campaigns and is in the process of removing the preapproval requirement from their quality system.

Change control approaches vary between companies, but there was agreement that systems in early development must be able to quickly address deviations and changes.

 Several companies manufacture externally and rely heavily on the CMO’s quality systems for documenting deviations.  In cases where the CMO manufactures both early- and late-phase/commercial supplies, it is advantageous to track the deviations separately for corrective action and preventive action (CAPA) purposes. It was noted during discussion that direct and timely quality involvement in early development should be encouraged to ensure that potential manufacturing concerns are quickly captured and addressed or dismissed.

	A second breakout session focused on the practices of extemporaneous preparations (EP). On-site formulation preparation is an effective means of preparing early clinical supplies.  In addition to shorter timelines, advantages of this approach include: lower DS demand, reduced analytical method and stability support, flexibility to quickly adjust dosing in response to clinical data, and less resource demand. According to an IQ working group survey, approximately 80% of companies already have the capability to do EP.  This approach, however, is only being used in approximately 20% of applicable applications. Full results from this IQ survey will be published separately.  Some obstacles companies have faced in implementing EP include: access to sites that can handle hazardous compounds or complex formulations, interpretation of regulatory requirements and regulatory authority expectations, and internal resistance toward “non-traditional” approaches.

	The breakout session included three short presentations covering the history of EP, regulatory requirements/strategies and case studies of successful on-site preparation of immediate- and controlled-release dosage units.

	While the preparation of EP material might not take place in traditional GMP manufacturing areas, it remains crucial that appropriate controls are in place to ensure subject safety and to safeguard product quality. Participants at the workshop agreed that safety is top-priority and that this responsibility ultimately resides with the study sponsor.  The sponsor quality unit should audit the compounding site. Industry participants discussed the importance of carrying out one or more practice preparations at the compounding site.  Industry participants discussed the practice of testing during and after these mock runs and using these data to validate preparation instructions, potentially eliminating the need to perform end-product testing on the actual preparations that will be given to study subjects. This approach allows for rapid dosing and de-risks changes that may occur in the product while waiting for analytical testing results.  If this approach is taken, it is still important to perform stability studies on the mock preparations to support a practical “use-period” for the product.  FDA representatives did not provide comment, but referred to the FDA guidance on testing expectations (7).

	The EP approach is not limited to simple powder-in-bottle or solution/parenteral preparations for ADME and absolute bioavailability. Companies have successfully used EP to study the effects of drug release rate on pharmacokinetics using controlled-release preparations.  Case studies from on-site preparations of matrix tablets as well as osmotic capsules were presented.  Results of these types of EP studies can be used to quickly answer questions about food effect, colonic absorption, or potential for reducing adverse events-while using only a small amount of DS.

	There was considerable discussion during the breakout session about regulatory expectations and filing strategy. EP practices rely on standards of quality in a clinical pharmacy, which are governed by local laws and good clinical practices.  Requirements for CMC submission vary country-to-country. For Singapore studies, no CMC information is typically provided to the Health Sciences Authority (HSA). Instead, someone from the HSA will visit the clinic or pharmacy to inspect preparation activities. For US studies, section P.3.3 of the investigational new drug (IND) application should include all of the key preparation steps and controls.  It was noted that in Europe, all compounding pharmacies are cGMP compliant, and EP are released by a qualified person (QP).  From a submission perspective, most companies treat EP clinical studies as “Phase I” even if the active ingredient itself is in later development or commercially available.  The studies are short in duration, are closely monitored, and often use low or sub-therapeutic doses. The EP studies are also often the first time that a formulation has been evaluated, and usually do not represent the intended Phase III or commercial product.

	Stability in early development workshop output

	Presentations and breakout sessions on stability in early development followed the elements and recommendations of the IQ paper on the subject (4). Some participants acknowledged that the industry may be currently performing a lot of non-value-added stability studies, and that most of the resistance to reducing stability testing comes from within the companies rather than from regulatory authorities. It was pointed out that companies should focus on accumulating product/process knowledge and use risk assessment to design only necessary stability studies, while being mindful of regulatory environments.

	Strategies in leveraging solid stress testing for drug substance and simple drug products like PiB (Powder in Bottle) and PiC (Powder in Capsule) were discussed. This practice is typically applied to stable and moderately stable DS, which is usually stressed at 70°C/75%RH for up to three weeks and at the 1X International Conference on Harmonization (ICH) Q1B photostability testing condition. Open containers to simulate the bulk (DS) least-protective packaging configuration are typically used, although some companies also stress the DS in closed containers to simulate packaged PiB and PiC configurations. Usually an initial DS retest period and an initial DP shelf life can be extrapolated to 15 months at 25 °C, with a range of 1218 months depending on companies’ internal policies and risk tolerance. The assigned retest period and shelf life (called “use period” for brevity) is then verified with reduced ICH long-term and accelerated stability testing of a “representative batch.”  With this approach, one company has achieved seven successful clinical trial application (CTA)/IND submissions with an EU country and FDA.

	Companies also shared their experiences in using the software ASAPprime, an Accelerated Stability Assessment Program (ASAP) modeling software, to enable rapid stability evaluations in early development. Employing several combinations of temperature and humidity conditions, ASAP is typically used to evaluate the chemical stability and thus to extrapolate a use period of DS and formulated DP. This model is also commonly used to assess the potential impact of packaging changes on material stability. Depending on the model data, it is possible to change to a less protective packaging without having to repeat stability testing. Physical changes are harder to predict with ASAP. Two companies have included ASAP stability data in regulatory filings with FDA and some EU countries. One company noted that some EU countries have expressed discomfort with ASAP-based extrapolation.

	How stability data from representative batches of DS or DP are used differed among companies.  Most companies use a non-GMP representative batch of DS or DP to get a more rapid assessment of the material’s stability. How stability studies are performed on the first GMP batch, however, varies across the industry. In some cases, when a representative non-GMP batch is placed on stability, GMP batches may be placed into stability chambers without testing. This approach would make the GMP materials on stability available for testing when there is a need to respond to regulatory queries, or if further development information gathered suggests that the batch is, in fact, not similar to the representative batch. Other companies conduct ICH long-term and accelerated-stability studies on the first GMP batches to use those batches as the stability representative batches.

	It was also noted that while changes to DS or DP processes may affect the quality of a new batch, they may not affect its stability. When changes to processes or materials are made, any potential changes to the stability-related quality attributes should be considered to determine if stability studies are warranted for the new material. This is commonly done using a stability risk assessment (RA). In general, companies use RAs to make stability-testing decisions for new batches of DS and DP after changes. The formality of the procedures used to follow and capture RAs varies across the industry. RAs tend to be less formal for early-stage development and more formal for late-stage development.

 36 (6) 54-58 (2012).
	2. D. Chambers et al., 

 36 (7) 76-84 (2012).
	3. R. Creekmore et al., 

. 36 (8) 56-61 (2012).
	4. B. Acken et al., 

 36 (9) 64-70 (2012).
	5. M. Coutant et al., 

Guidance for Industry: cGMP for Phase 1 Investigational Drugs

	Q. Chan Li, senior principal scientist, Boehringer Ingelheim
	Jackson D. Pellett, scientist, Genentech
	Michael Szulc, principal scientist, Biogen-Idec
	Mark D. Trone, director, Alkermes
	Kirby Wong-Moon, principal scientist, Amgen

GMPs for Small-Molecule Drugs in Early Development: Workshop Summary-Part VI

	The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ) formed in 2010 is an association of over 25 pharmaceutical and biotechnology companies with a mission to advance science-based and scientifically-driven standards and regulations for medicinal products worldwide. In the June 2012 issue of 

, a paper was provided which described the IQs Good Manufacturing Practices (GMPs) in Early Development working group (1). This working group (WG) is focused on developing recommended approaches to applying GMPs in several areas of Early Phase CMC development activities (e.g., Phase 1 to Phase 2a). A key premise of the GMPs in Early Development WG is that existing GMP guidance documents for early development are vague and that improved clarity with options to meet GMP expectations would be helpful. Although more prescriptive guidance is not advocated, the sharing of best practices in this paper is done herein to advance innovation in drug product development by improving cycle times, while maintaining appropriate product quality and ensuring patient safety.

	A consequence of the absence of clarity surrounding early phase GMP guidance has been varied interpretation and application of existing GMP guidance within different companies and regulatory bodies according to their own culture and risk tolerance. Internal debates often result in conservative "one-size-fits-all" interpretations that rely on International Conference on Harmonization (ICH) guidelines that are relevant to commercial product development and do not distinguish differences in practices between early development and later-stage development (i.e., Phase 2b and beyond). A key driver of the IQ WG, therefore, has been to collectively define the minimum acceptable practices within industry regarding GMP expectations in early development that allow for added flexibility and that are consistent with existing guidance and statutes (2, 3).

	As outlined in the introductory paper to this series, the efforts of the GMPs in Early Development WG have been focused into the following four areas of Chemistry, Manufacturing, and Controls (CMC) activities: Analytical Method Validation, Specifications, Drug Product Manufacturing, and Stability (1). The initial scope of these efforts has been limited to small-molecule development, which support First in Human (FIH) through Phase 2a (proof-of-concept) clinical studies.

	A series of whitepapers describing a recommended approach to applying GMPs in each of these areas is being published within this journal. In past editions, approaches to Analytical Method Validation, and Manufacturing to support health authority submissions were provided (4, 5); approaches to Specification setting will be published in the October 2012 issue of 

	In this paper, Part IV, stability needs are discussed. During early drug development, stability data can be generated to support the manufacture and storage of clinical products to meet regulatory expectations for Investigational New Drug (IND), Investigational Medicinal Product Dossier (IMPD), or Clinical Trial Application (CTA) filings and to help understand the product and process. The authors illustrate some best practices for stability to support early phase clinical trials in this paper; however, some companies may choose to do more, or possibly less, at their discretion and with appropriate science- and risk-based justifications suitable for the phases and purposes of development. The GMP quality systems (e.g., chamber qualification, standard operating procedures) used to support such studies are not the focus of this paper.

	Stability studies to support early phase development

	Early in development, pharmaceutical research organizations develop products with a primary focus on patient safety. Data are generated at appropriate storage conditions to demonstrate or support the stability of the drug substance and product to assure product quality through the clinical study period. Guidance documents are available to indicate the type of information needed to support clinical trials (3, 6–8). Although ICH stability guidelines outline the stability data needed to support storage conditions and shelf life for commercial submissions, these guidelines are not applicable to early stages of development when less is known about new drug substances and products (9). However, there must be appropriate data to support storage of the products being proposed for clinical use.

	If a product is intended for human use, the concepts of cGMPs apply. For stability, this application often results in a written stability study plan or protocol, fit-for-purpose test methods, traceable and reliable documentation, and appropriate SOPs. Most compounds in early development end up being discontinued, for safety and/or efficacy issues and/or inadequate commercial viability. Therefore, efficiently assuring the quality of products being used in early human clinical trials is a challenge facing every pharmaceutical research organization involved in early trials. The common challenges faced in supporting drug substance (also referred to as API) and drug-product stability are discussed here. The authors offer some risk-based approaches for collecting data for small molecule, solid oral dosage forms used in Phase 1 and Phase 2a clinical trials, in hopes of guiding companies and health authorities towards harmonized strategies and best practices.

	In early phase development, CMC requirements include generation of appropriate stability data at suitable storage conditions to support filing the IND (or IMPD/CTA) and use of the clinical material through the end of the clinical study. These scientific and regulatory objectives for stability must be met while at the same time minimizing nonvalue-added operational expenses. Several factors from a business, regulatory, and scientific perspective need to be taken into account when designing early phase development stability studies:

		The risk tolerance of the sponsoring organization and their approach to the scientific mitigation of the risks.

		The inherent stability of the drug substance or product, and prior product, process and stability knowledge.

		The regulatory environment in the countries where the clinical trial will be conducted. For example, some countries may request stability data on multiple batches or actual clinical batches or may not accept extrapolation to justify use-date assignments.

		The projected future use of the product. Development teams may have some idea of the likelihood that a project will continue into Phase 2b. If a product is expected to be used for many months or multiple years through several development phases, then a use-date extension proposal based on additional long-term data may be necessary and further knowledge gathering may be warranted (3). This information may influence the scope of the initial stability study in the form of additional time points, additional conditions, and/or additional tests.

	Considering these factors, the industry must work to balance the perceived expectations of the regulators in the countries where clinical trials will be conducted using a science- and risk-based approach to generating and providing stability data in the regulatory filings.

	Discussed in this article are recommendations with regard to generating stability data for drug substance and solid oral dosage forms used for Phase 1 and Phase 2a (early phases of development). This paper presents a framework and guiding principles to this end. The examples presented are not meant to be a "how to" guide, but rather illustrations of the principles being discussed. Other study designs and conditions may also be feasible with the appropriate justification.

	The product development efforts for early clinical supplies often are simple formulations with limited development history. The early small-molecule oral products can be placed into one of two categories: drug-substance (DS) based products and formulated products. DS-based products include the use of neat DS (e.g., powder-in-bottle [PIB], powder-in-capsule (PIC), or DS shipped in bulk to clinical sites for on-site compounding). These products almost always have the same stability characteristics as the bulk DS, and DS stability data may be used to support the product use dating. Formulated products can be powders formulated with excipients, capsules filled with formulated granulation, or a tablet formulation. These formulations take more effort and are normally used because of a specific clinical need, a shortcoming of the DS-based product, or a desire to use the same formulation in Phases 1 and 2 studies. In most cases, they will be fairly simple formulations meant to have a short lifecycle. If the product advances further into development, more elegant formulations will need to be developed. Not covered in this paper are formulations that are extemporaneously prepared at the clinical site. These formulations are consumed quickly and long-term stability studies are not warranted.

	In the following sections, DS and drug product (DP) stability considerations for early development are discussed.

A representative batch of DS, or DP, is one that is expected to have similar stability to the batches used in clinical production, based on a science- and risk-based assessment of attributes expected to influence stability and knowledge obtained during development. Often non-GMP or GLP (good laboratory practice) DS batches are manufactured first and placed on stability to support a variety of product development activities. These batches often are representative of GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. Stability data included in the CMC section are limited at this stage of development (5). The DS batch used for Phase 1 clinical supply manufacture may be placed on stability concurrent to the clinical trials, if additional study is warranted.

	In early development, it is common for the manufacturing process to be improved as a normal part of development. As the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted. The basic principles are discussed below and further details of such an approach can be found in Ref. 10 and its citations (10).

	The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge (as discussed in the next section) comparing the new batch with the earlier batch. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability. If the revised process does not result in a change to a stability-related quality attribute, the new batch does not need to be placed on stability. There are certain changes that almost always require a new study. Different polymorphic form, counter-ion, or solvate forms of a compound cannot be assumed to have the same rates of degradation or the same degradation pathways. Therefore, these changes will almost always require new stability data (11).

	Typical changes encountered in early development include changes in synthetic pathway (including a change in the order of the bond forming steps), batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps. In most cases, these changes will not result in changes in DS stability. A common misconception is that changes to the impurity profile will adversely affect stability. Most DS impurities, particularly organic impurities, are essentially inert and have no effect on DS stability. Some impurities, such as catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents, may affect stability, and if the new process changes the level of these impurities, additional stability may be warranted. Packaging changes of the bulk material to a less protective package may require stability data to support the change. Likewise, changing to a more protective package in order to extend the retest period, beyond what the original representative batch study could support, may require additional data in the new package.

	Physical attributes that may impact stability include particle size/surface area, the degree of crystallinity/amorphicity, polymorphic form, hydrate form, and moisture content. If a new process changes any of these attributes, a risk assessment is recommended to determine whether additional stability is warranted. In some cases, short-term accelerated or stress stability data can help decide if these attributes are in fact stability related quality attributes. The concepts detailed in the above two paragraphs attempt to differentiate major and minor changes and may result in different stability strategies to support these changes.

	A risk assessment may help to determine whether the current batch is sufficiently representative. Alternatively, additional data may be needed when the batch is not representative or when there is substantial doubt after the assessment.

Drug-substance stability data collection. 

Although the stability testing practices and the amount of collected data vary from company to company, three commonly used approaches are discussed here. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH) and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). If needed, the stability study can be continued to extend the retest period or the GMP material can simply be retested, as needed, as part of a retesting program commonly used for manufacturing components.

	The selected analytical tests for stability studies should cover the quality attributes related to stability. Typically, these tests would include impurities and description and may include assay. Chiral purity, polymorphic form (e.g., x-ray), and water content should be tested, as appropriate. It may not be necessary to perform all tests at every time point depending on the purpose of the test.

	A second approach is to use high stress conditions with a short time such as a high temperature and high humidity (HT/HH) model. For example, the DS is stored at 70 °C/75%RH in open and closed containers, while monitoring the chemical and physical stability up to three weeks. The chemical stability results are used to extrapolate the initial DS retest period up to 18 months, more or less if justified. The extrapolation is based on the principle of the classic Arrhenius relationship between temperature and the reaction (degradation) rate, assuming a pseudo-zero order reaction. It is a simple and fast prediction of DS stability (12). This approach is most applicable for DS that is considered to have good physical and chemical stability as demonstrated during drug discovery. Acceptance of this approach has been gained in a number of filings.

	A third approach is the use of stress studies at several conditions coupled with modeling, such as the Accelerated Stability Assessment Program (ASAP) (13). ASAP combines an accelerated aging protocol with a humidity-corrected Arrhenius equation to provide an early prediction for DS and DP use period. It involves statistical analysis for more complex modeling of non-single order kinetics of degradation in DS and DP, and it produces faster and reliable predictions of chemical stability. For DS or DP with potential chemical stability challenges, this approach can be very useful to define appropriate storage condition and use period within a relatively short time to enable progressing early development programs. More importantly, ASAP has potential for a broader scope of stability assessment for developing control strategy of DP stability, such as long-term stability prediction and packaging requirements in implementing QbD for commercialization. ASAP has been used by companies as part of regulatory filings in multiple countries and has provided the basis for formulation, packaging, and moisture content justifications. There is an ongoing dialog between industry and regulatory agencies about these newer ways for industry to meet its obligations with respect to assuring the acceptability of products at the end of their shelf lives.

	The knowledge gained from these studies can then be used to: support storage conditions and initial retest period assignments; design future stability studies; assess the impact of temperature excursions; and select packaging. The results can also be used to establish the initial use period for DS-based products (e.g., PIB or PIC). The accelerated or stress approaches may save time in arriving at a first estimate of a material's stability.

	The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

Drug substance stability data, commensurate with the stage of development, can be generated to support use of the DS to manufacture clinical supplies through a system using retest dates. When a longer retest period is needed, the extensions are most commonly handled either through a stability program or through a batch-specific retest program. Wording may be provided in filings to outline how the retest period will be extended in the future. If using stability data from the second (HT/HH) or the third approach (ASAP), a retest period is extrapolated from the Arrhenius equation or moisture corrected Arrhenius equation (12). Stability testing also is used to support use period dating of simple DS-based products.

	Design of drug-product stability studies for early development

As noted earlier, early stage clinical supplies often are simple oral formulations or powder-in-bottle or powder-in-capsule. Stability studies at this early stage need to support the use of the product in the clinical studies and to facilitate further development. Unless a specific formulation is required for early phase studies (e.g., due to poor solubility, poor bioavailability, the need for once-a-day formulations, or the need for a sterile injectable formulation), a simple oral solid-dosage form is typically employed. For the DS in capsule or bottle, stability of the DS will support early stage development, however, the clinical supply may be placed on stability (e.g., retained samples) and tested, if necessary. The study would continue through completion of the clinical study and could also be monitored at later time points to increase product knowledge, if appropriate.

	For formulated oral solid-dosage products, preformulation and process development studies can be performed to define the initial formulation. These studies will also provide initial stability information on the DS and its compatibility with excipients, moisture, processing conditions, and so forth. At this stage, a development batch (non-GMP) may be manufactured and placed on stability. If this batch is representative of the clinical supply (same or closely similar composition, process, and packaging) it can support the IND/IMPD filing and the initial use date for the product. If more than one strength is required, a bracketing stability design can be used. Changes to the clinical drug product need to be evaluated and additional batches placed on stability, as necessary. Using the same tools and thought processes that were mentioned in the DS portion of this paper, the first step is to determine what DP attributes have an effect on stability. If the new DP changes one or more of the stability-related quality attributes, the new batch should be placed on stability. Identification of these stability-related quality attributes can be facilitated through paper-based risk assessments, prior knowledge, or through short-term stability challenges. Changes that could impact product stability include major DS changes (e.g., solid form), formulation changes (e.g., drug to excipient ratio, different excipients), significant process changes (e.g., direct compression to wet granulation), and packaging changes (e.g., contact materials, blister versus bottle, change in size/headspace). Changes unlikely to affect stability for simple oral dosage forms include changes in scale, equipment, and site of manufacture.

	Minimum requirements for a stability study to support early filings

Typically, there are limited batches in early development. Because these clinical studies are small, there is often a need for only one batch to be produced. For clinical materials expected to be used only through Phases 1 and 2a, the authors believe long-term data collected on the clinical batch or a batch representative of the clinical batch may be sufficient to ensure stability of the clinical product in early phase development. For stable products, additional batches of the same formulation do not need to be placed on stability.

Studies should generate data that give assurance that the clinical supplies retain their quality within acceptable limits at least through the use of the supplies in the clinic. Because early stage clinical studies can be relatively short, stability data need only support short-use periods. However, in many cases, extra samples are in reserve to extend studies for longer duration as a matter of practicality; for example, if the supplies are needed for longer duration than initial plans due to delays in the clinical program.

	As noted, the ICH Q1A guideline on stability testing includes recommendations for stability studies for market application requirements but these are not meant to support early clinical trials. However, many of the ICH constructs are still useful such as the storage conditions and spacing of the time points. Spacing of the time points should be designed to capture the overall stability trend, noting that having a few earlier time points during screening studies or more formal stability studies to establish a use date by the time of filing can be desirable.

	For DP, the early phase formulation usually will not be used in later clinical trials. As such, there is little value to carry the stability study beyond the time in the clinic.

	The selected analytical tests for stability studies should cover the quality attributes that may change with time. Typically, these tests would include assay, impurities (i.e., degradation products), drug release (e.g., disintegration or dissolution), and description. If chiral conversion has been shown to be an issue in DS then it should be monitored in DP. It may not be necessary to perform all tests at every time point depending on the purpose of the test.

	Data fromHT/HH stress studies may be useful in impact assessment for temperature excursions and to design efficient long-term studies. Another approach is the stress studies coupled with modeling, such as ASAP as discussed above. ASAP in some instances can give a good use period estimate in a shorter time than the traditional long-term stability approach. The use date derived from stress-extrapolation can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long term conditions.

Strategy for use dating and use-date extensions. 

Extrapolation of use periods is a commonly accepted practice and nearly a necessity in terms of getting clinical product packaged, labeled, released, and shipped to clinical sites with some use time remaining for storage at clinical sites. There has been much debate on how extrapolation of existing stability knowledge should be used to set use periods of clinical supplies. As was discussed at the beginning of this article, many factors will determine the amount of extrapolation that is defendable. Health authorities may be reluctant to accept extrapolations of more than 12 months past the existing long-term stability data, but it is possible to justify more or less extrapolation based on scientific grounds (see section on DS stability data collection). A one-size-fits-all approach is difficult to arrive at in terms of an exact number for allowed extrapolations, but an approach based on science and risk management is recommended.

	With sufficient DS and drug product stability knowledge and a stable clinical formulation, the risk to the quality of the material is low when allowing for stability retest/use period extensions 12 months beyond available real-time stability data. This, however, would not be appropriate for an unstable drug product or one for which there is insufficient stability knowledge. This risk-based approach is based on three principles:

		Stability attributes that limit shelf life are determined from early development studies and appropriate packaging and storage conditions selected.

		Use-date assignments are monitored and confirmed though traditional (real time and accelerated) stability studies and appropriate actions taken if required.

		Companies have internal procedures describing processes for setting and extending initial use dates. Internal procedures for updating use-date assignments normally involve coordination of clinical relabeling and in some cases CMC filings.

	It is worth stressing the point that stability data first included in regulatory filings are often just the beginning of a program to monitor the stability of the clinical supplies and continued monitoring to confirm storage claims and initial trends can be very useful for products that continue development.

	The authors support the following recommendation from A. Kane: Companies often struggle with the strategy for updating retest/use period assignments throughout development and the consequent updates to the CMC submissions for IMPD and IMPD type dossiers. "Arguably the preference of many applicants would be to update assignments as more stability data are generated without the need for submission of a substantial amendment. To avoid the need for subsequent substantial amendments, the IMPD should contain the proposed specification and provide a clear explanation of how extrapolation is/will be applied to assign the retest/use period assignments" (14). It is the authors' belief that with a well-planned monitoring program, extrapolation with limited initial data is justified.

	Demonstrating stability for clinical supplies should be driven by scientific knowledge gained in development as well a risk-based assessment to guide efficient use of available resources. In early development, clinical efforts are often focused on relatively simple products with short life cycles and the DS from which they are made are often produced by evolving chemical processes. The efforts to determine the stability of the DS and drug product should be fit for this phase of development and are designed to give the most basic stability information, namely, to ensure that the DS is of suitable quality when used to manufacture product and that the drug product is of suitable quality while in the clinic. To make this assessment, simple stability studies using ICH constructs and/or accelerated or stress data may be used. Other experimental data may be collected to increase the scientific knowledge of the DS/DP.

	It is our hope that providing the approaches to early phase stability outlined here, along with the approaches in this series of white papers by the other focus areas of the IQ Early Phase GMPs working group, will provide a springboard to stimulate discussions on these approaches within the industry and with worldwide health authorities.

	To encourage further dialogue, this IQ working group is planning a workshop in the near future to promote robust debate and discussion on these approaches. These discussions will hopefully provide improved alignment between development, QA oversight, and regulatory within the pharmaceutical industry, and most importantly with worldwide health authorities. Agreement between industry and health authorities regarding acceptable approaches to stability studies in early phases of drug development would clearly be beneficial to development scientists and allow for a more nimble and flexible approach to better address the dynamic environment typically encountered during the early phases of clinical development, while still providing appropriate controls to ensure patient safety.

	This article represents the opinion of the authors and not necessarily those of their respective companies.

 is in Analytical Sciences at Merck & Co. Inc. (Summit, NJ); 

is in Pharmaceutical Analysis and Microbiology at Allergan (Irvine, CA); 

 is at Pfizer Global Research and Development (Groton CT); 

is in NCE Analytical R&D at Abbott Laboratories (Abbott Park, IL); 

is in Pharmaceutical Development at Endo Pharmaceuticals (Chadds Ford, PA); 

 is in Pharmaceutical Development, both at Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT); 

 is in Analytical and Bioanalytical Development at Bristol-Myers Squibb Company (New Brunswick, NJ); 

is in Analytical Science at Astra Zeneca R&D (Macclesfield, UK); 

 is in Analytical R&D at Amgen (Thousand Oaks, CA); and 

	*To whom all correspondence should be addressed.

 Part 211.166 Stability Testing.
	3. CHMP, CHMP/QWP/185401/2004, Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (EMA, Mar. 31, 2006).
	4. D. Chambers et al., 

 (7) 76–84 (2012).
	5. R. Creekmore et al., 

Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology Derived Products 

(Rockville, MD, November 1995).
	8. FDA, 

Guidance for Industry: INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls 

(Rockville MD, May 2003).
	9. ICH, Q1A(R2) 

Stability Testing of New Drug Substances and Products

, Step 4 version (2003).
	10. S. T. Colgan et al., "The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies," 

(in press 2012).
	11. S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, Solid-State Chemistry of Drugs. 2nd Edition (SSCI, Inc., West Lafayette, Indiana) pp. 259–366. Also see, ICH, Q6A, 

Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

, Step 4 version (1999).
	12. K.C. Waterman, "Understanding and Predicting Pharmaceutical Product Shelf-life" in 

Handbook of Stability Testing in Pharmaceutical Development

, K. Huynh-Ba, ed. (Springer Science Business Media, LLC, New York, NY, 2009) pp. 115–135.
	13. K.C. Waterman, 

 (3) 932–937 (2011).
	14. A. Kane, J. Williams, and L Yeo, 

IQ Consortium representatives explore and define common industry approaches and practices for applying GMPs in early development, with a focus on stability.