Kirby Wong-Moon

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 authors, part of the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium), explore and define common industry approaches and practices when applying GMPs in early development. A working group of the consortium aims to develop a set of recommendations that can help the industry identify opportunities to improve lead time to first-in-human studies and reduce development costs while maintaining required quality standards and ensuring patient safety. This article is the fifth paper in the series and focuses on specifications.

	The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) was formed in 2010 as 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 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 Good Manufacturing Practices (GMPs) in Early Development (Phase 1 through Phase 2a) (1–4). In this issue of

, the IQ Consortium presents a proposal for the analytical assessment and control of both drug substances (DS) and drug products (DP) in early development specifications. These recommendations take into consideration the differences in clinical trials in early development versus those in later development and provide a starting point to stimulate discussion on specifications in early development.

	Previous industry position(s) on the topic of science-based specifications have not addressed early development needs or differentiated the role of specifications in early versus late development (5). During preclinical and early development, the primary focus is to progress the product into the clinic for safety and preliminary efficacy assessment. Due to the high attrition rate in early development, consistent specifications that ensure patient safety are desirable. During late development, specifications evolve as the clinical focus expands from safety to include efficacy, and as the product and corresponding synthetic and formulation process undergo significant transformations (e.g., synthetic route changes during scale-up, evolution of dosage forms from fit-for-purpose to robust formulations and processes suitable for commercial manufacturing). Therefore, early development specifications should also focus on those tests and acceptance criteria determined to be critical for the control of product quality with an emphasis on patient safety and supported by preclinical and early clinical safety studies.

Based on the cumulative industry experience of the members of this IQ working group, the authors of this paper have proposed standardized early phase specification tests and acceptance criteria for both DS and DP, which are discussed herein. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications. These tests can be performed to collect information for product and process understanding, or to allow for tighter control (i.e., target criteria tighter than the release testing criteria), to ensure product quality will be maintained throughout the product's retest period. Based on the information obtained in early development, additional tests and acceptance criteria for other attributes (e.g., water content) can be included as the late development focus shifts to process and product performance and consistency; eventually aligning with the available ICH guidelines (6).

	The scope of this position paper has purposely been limited to traditional small molecules that are formulated into solid oral dosage forms intended for US regulatory filings with the desire to build consistency across all worldwide regulatory regions. However, it is believed that the concepts presented can be easily adapted to other dosage forms and routes of administration. Although designed as an industry proposal, it is recognized that each company needs to evaluate these DS and DP specification recommendations based on their individual business needs.

	The DS used in the first-in-human (FIH) enabling GLP drug safety studies, referred to in this article as the "tox batch," is a fundamental part of the product lifecycle in defining the specifications for an early phase clinical DS. For the DS used in the tox batch, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities, structural identification, process purging capabilities, rework processing procedures, and potential impact to the safety study. The DS tox batch is typically subjected to a series of tests to confirm description, identity, potency, and purity. The main goals are to:

		Ensure that the correct DS is administered to the test animals (often done via a spectroscopic analysis such as nuclear magnetic resonance or infrared)

		Determine the correct potency value of the DS to ensure the proper dosing of the animals

		Quantitate impurities for toxicology qualification.

	For DS intended for clinical studies, additional testing and controls beyond those used for the GLP toxicology lot testing may be required. The testing may be similar to the DS tox batch, but with established acceptance criteria. In early development, the depth of knowledge regarding the synthetic route is still evolving and the DS has not been fully characterized. Accordingly, the initial clinical acceptance criteria are often based on target specifications (see 

), with the safety limits established from the tox batch being evaluated during the disposition process of the GMP clinical DS. If the tox batch is also inten

	ded to be used in a clinical study, there is an advantage in that the qualification of impurities for the clinical studies is inherently assured. In this case, the formal specification for clinical disposition of the DS may be established based on the results of tox batch testing. To further highlight the differences in expectations for early phase DS specifications, the authors propose a standardized set of clinical DS specification attributes in the following sections.

Description, or appearance, is a test describing the visual attributes of the DS. Although technically simple in terms of the test, it can be the subject of much discussion due to potential discrepancies in visual observations from analyst to analyst. Important aspects of this specification are to ensure that there is no visible contamination or anomalous appearance within the DS. The recommended early phase acceptance criteria is often a somewhat broad range of colors (e.g., "white to almost-white to light yellow powder") because there is typically little batch history in early development related to the color of the DS. If it is known that the DS has an inherent color, the specification should be adjusted accordingly.

 At least one form of discerning chemical identification (ID) testing is performed in the early clinical release DS specifications. This testing ensures that the drug being dosed is traceable to the same chemical entity that was qualified in the safety studies. A single ID test by a spectroscopic method such as IR is often employed. Often, the spectroscopic method compares the DS with a known batch that has been well characterized by several analytical methods.

The counterion, if present, often is a relatively large percentage of the DS and as such is important to understand the overall potency. The recommended acceptance criteria is "report results" while batch data is accumulated and the variability of the analytical methods is assessed. If the DS is sensitive to extreme counterion levels (e.g., changes in hygroscopicity), internal targets may be implemented to prospectively alert the internal product development team of any potential issues.

Assay is a critical DS component used to determine the accurate dosing concentration for the corresponding clinical DP. The recommended range is 97.0% to 103.0% (wt/wt on a corrected anhydrous basis) based on typical assay variability for an HPLC-UV method and an acceptable accuracy range required for the early phase clinical studies. This range may be modified with justification for particular circumstances that require a wider acceptance range (e.g., elevated levels of a qualified impurity). In the absence of a reference standard, which may be the case for the initial DS lot, the assay value may be derived by using an assigned chemical potency factor that takes into account related substances, residual solvents, moisture, counterion, and inorganic impurities present.

Controlling organic impurities and degradation products through the DS specification is required during all stages of drug development, except in initial microdose studies. As discussed, understanding the profile of impurities qualified in the Tox batch is crucial to establishing acceptance criteria for impurities in early phase clinical DS. It is also important to monitor degradation products and impurities present in the clinical DS which may not have been qualified in toxicology studies.

	In early phase development, there is limited exposure to the clinical candidate and low numbers of individuals participate in these early clinical studies. The risk to patient safety is relatively low compared to late stage development (7, 8). Therefore, this IQ working group proposes controlling impurities in early stage DS at levels that are three times (3X) higher than those defined in ICH Q3 guidelines (9, 10). As clarified in the preamble of these guidance documents, the ICH impurity guidelines are intended for pharmaceuticals approaching the point of final commercial application submission. It is inappropriate to apply these commercial ICH expectations during early clinical development based on the shorter duration of exposure during these earlier clinical studies. This 3X ICH recommendation for DS impurities in early development translates to a qualification threshold for individual impurities being three times the commercial ICH Q3A limit. Specifically, the early phase DS impurity qualification threshold is proposed to be 0.5% or 3 mg per day intake, whichever is lower, for a maximum daily dose ≤ 2 g/day. It is recognized that individual companies within industry may choose to apply different impurity qualification thresholds in early development based on an assessment of safety in the context of the individual development program.

Similarly, an identification (ID) threshold of three times the ICH Q3A limit (0.3%) is proposed for unknown impurities that have not been qualified by toxicology studies. This ID threshold can be set higher for unknown impurities that have already been qualified. It is expected that as development progresses, impurities would be assessed from a toxicological perspective, appropriately qualified as necessary, and the relevant specifications updated accordingly. Later in development (Phase 2b and beyond), when a larger patient population is exposed to the clinical candidate for longer durations of time, the DS specifications for unqualified impurities should be narrowed to approach the limits outlined in the commercial ICH guidelines. 

 provides examples of various impurity scenarios to illustrate the utilization of the proposed early clinical identification and qualification thresholds and their potential impact on the acceptability of several example DS lots. All of the included examples assume a maximum daily dose of < 2 g/day and that the individual impurities are nongenotoxic.

	For individual impurities that exceed the 0.5% threshold but are supported by toxicology data, an upper limit of not more than (NMT) 1.0% in the DS is appropriate for this stage of development. In some situations, an upper limit greater than 1.0% can be justified if the impurities are qualified at a higher level or if it is evident that the specific compound is also a known metabolite. In either case, a close review of the impurity profiles is required to ensure the quality of the clinical lot(s) is appropriate for the intended use and comparable based on projected exposure levels to the tox lot impurity profile. This may be triggered through the use of internal targets with alerts corresponding to the identification or qualification levels discussed above. For total impurities, the acceptance criterion often correlates with what is known about the individual impurities. An upper limit of 3.0% for total impurities is proposed as suitable for this stage of development. However, a higher upper limit for total impurities may be justified if there are a number of qualified impurities present in the DS.

Chiral impurities are usually held to the same criteria as any other impurity or degradation product with a known structural identification, leading to a proposed specification of NMT 1.0%. However, the target limit for the minor enantiomer can vary based on understanding of its pharmacological activity, toxicological qualification, metabolism pathway, and purging capabilities of the synthetic process. Sometimes it is difficult to determine the absolute chiral purity of a DS that has multiple chiral centers due to chromatographic separation challenges. For these molecules, specific rotation can be used to monitor the chiral purity in early as well as late development. Another acceptable approach to controlling chiral impurities in the DS is to monitor the chiral purity of the starting material or at an intermediate stage, where the corresponding isomers can be readily prepared and chiral chromatographic methods developed.

 The early development specifications for residual-solvent control are often set using the ICH established limits, including the consideration of maximum daily dose for Class 2 solvents (Option 2) (11). If the residual-solvent levels are likely to exceed the ICH limits, the specification limits in early development may be set higher than these ICH limits if they are realistically based on the manufacturing process capabilities and if there is low toxicity potential (e.g., Class 3 solvents that form solvates with the DS). In lieu of setting the standard ICH acceptance criteria, evaluation of known safety data are normally provided and justified by the appropriate drug-safety organization. It is also common practice to only set acceptance criteria on non-Class I solvents used in later steps of the synthetic process (e.g., final recrystallization and last synthetic steps) while assuring all solvents are purged through internal/characterization testing of intermediates and/or final DS.

	In addition to the specification tests already described, there are several tests routinely performed but not included in the specifications that are designed to gather information on the DS as the compound advances through process and analytical development. These tests are often linked to process consistency, and in early phase development there is sometimes a temptation to set wide limits based on limited manufacturing experience. Instead, it is recommended to gather data through internal/characterization testing as manufacturing experience is gained. These tests may become part of the formal specifications when meaningful limits can be introduced based on experience with the compound. These additional characterization tests are discussed below.

Limits for mutagenic or potentially mutagenic impurities have been the subject of much discussion among the industry because ICH is currently drafting its M7 guideline on this topic (12). While the landscape for this class of impurities continues to evolve, the recommendation is to follow existing guidances, such as the 2007 CHMP Guideline on the Limits of Genotoxic Impurities, until ICH M7 is finalized (13).

Inorganic impurities are typically monitored 

 Residue on Ignition (ROI) and heavy metals tests using 

) General Chapters <281> and <231>, respectively. The recommendation for ROI in early development is an internal specification of NMT 1.0% with the knowledge that this specification may be tightened as development progresses. The current 

 heavy metals test is not typically sensitive to many of the metals used in an DS synthetic route and is also currently scheduled to be retired in the near future. As such, residual metals are often monitored internally by inductively coupled plasma–mass spectrometry (ICP–MS) or ICP–atomic emission spectroscopy (OES), or some other metal specific test. The recommended limits for these metals are those set forth in EMA guidance (14). This guidance provides classifications and permitted daily exposures (PDEs) for many of common metal catalysts and metal reagents. Limits for metals not contained within this guidance should be discussed with the internal product development team and appropriate drug safety organization.

Water content, polymorphic forms, and particle size. 

The proposed internal specifications for water, polymorphic form and particle size distribution (PSD) are all "report results" for compounds in early development. For water content, there is normally limited information available about a compound's sensitivity to moisture in early development. Although it is important that data be collected, initially the acceptance criteria should be "report results" unless the product quality is known to be sensitive to water. In the case where the DS is a known hydrate or shown to be hygroscopic, a target water content range is typically established in the DS specification.

	X-ray diffraction, Raman, and solid-state NMR can be used to monitor the polymorphic form of the DS. Because the polymorphic form can impact on solubility, stability, and bioavailability, any change in form is typically monitored during stability studies.

	Particle-size distribution (PSD) can be crucial to the ability to formulate the DS into the desired dosage form. In early development, many of the formulations are relatively simple (e.g., powder in a bottle) and the PSD information is normally gathered for development purposes only as an internal test. However in certain cases (e.g., low dose tablets, inhaled products), it is worth considering a suitable PSD target which is normally set in collaboration with the formulation development group.

Other tests may be considered as additional specification tests or non-specification tests for data collection purposes. For example, certain physicochemical properties of the DS, such as pH of an aqueous solution, melting point/range, and refractive index may be considered depending on the physical nature of the DS and its intended use. Similarly, there may be a need to specify the total count of aerobic microorganisms, the total count of yeasts and molds, and the absence of specific objectionable bacteria (e.g., 

) in the DS. If so, these should be suitably determined using pharmacopeial procedures.

	Quality attributes that affect DP performance are typically not known during the early stages of drug development. Regulatory specifications should focus on ensuring that accurate and reproducible dosing can be achieved in the clinic and that patient safety is not compromised. For many tests, it is important that characterization data be acquired, reported, and monitored to gain an understanding of the DP in the context of characterizing chemical, processing, and packaging sensitivities. As product development continues, the DP formulation and process, along with the corresponding analytical methods usually undergo significant changes. The specifications evolve as additional knowledge is gained (e.g., tightening or widening acceptance criteria, adding tests).

	As mentioned in the introduction to this paper, the authors have purposely limited the scope to oral dosage forms with an emphasis on US filings. The following sections outline proposed specifications for powder-in-bottle (PIB), powder-in-capsule (PIC), and tablets and capsules used in early development.

Powder-in-bottle and powder-in-capsule specifications. 

The PIB formulation is the simplest presentation of a DP for early clinical trials. It involves extemporaneous compounding of the DS into a solution or suspension for oral administration. The development of PIB requires a solubility assessment of the DS and selection of a pharmaceutically acceptable vehicle based on the expected clinical dose range. The DP is then manufactured by weighing the DS into appropriately sized bottles for reconstitution with the chosen vehicle at the clinical site. With the selection of PIB for clinical trials, the product development resources and timelines can be reduced significantly as there is no formal formulation development and thus additional analytical testing for stability, content uniformity, and dissolution are not necessary.

	Because only neat DS is weighed into the bottles, the specifications for the release of the DS can be readily used to release the DP. Thus, the results of the appearance and identification tests used initially for releasing the DS can be used for the DP as well. Similarly, the initial impurity results for the DP are normally taken from the DS release data and the degradation products are monitored as part of the recommended DP stability assessment. For PIB assay, the 90.0–110.0% range covers the typical variability observed in fill weights for this formulation. A stability study of the reconstituted PIB is normally conducted to support its use at the clinical site within the recommended storage conditions, as well as holding and dosing times.

	Verifying the uniformity of the dosage units is recommended as an internal specification test only. In PIB cases where it is intended to be weighed at the clinical site, a simple weight check during release testing assures that sufficient DS is contained in the bottle. This weight check may be omitted from the DP specifications if it is conducted as part of an in-process control. In cases where the entire contents of the PIB are to be used to make the clinical dosing solution and only a small amount of material (e.g., 1–2 mg) is provided in the bottle, then a more suitable quantitative analytical technique (e.g., a chromatographic method) may be required to verify the accuracy of the dosing concentration.

	Similar to PIB, the PIC formulation is another simple presentation of neat DS in a capsule. PIC also provides dosing flexibility but has the added advantage of allowing easy manufacture of matching placebos. The only major difference in its development process compared with PIB is that a compatibility study of the DS with the capsule shell should be done to select a suitable capsule.

The typical PIC specification tests used in early development are comparable to those used for PIB formulations (see 

). Specifically, appearance, identification, and assay all rely on the DS release results. Uniformity of PIC dosage units is performed according to 

 General Chapter <905> but it can be omitted as a regulatory specification if it is part of an in-process control. In addition, disintegration test per 

 General Chapter <701> is recommended to ensure that the capsules rupture to allow the release of the drug for absorption.

In early development, tablet and capsules for oral administration often employ "fit-for-purpose" formulation approaches designed to be suitable for wide classes of compounds, with the ultimate goal of facilitating rapid entry into FIH clinical trials. In the case of tablets and dry fill capsules (DFC), these formulations often employ a dry blend or granulations of a nonreactive diluent, a disintegrant, and a glidant to aid in processing. As shown in 

, standardized specifications are frequently established for capsules and tablets that are used in early development that can be segregated into the following attributes:

	Description and identification: Visual description of the dosage form and correct identification of the active dose are critical to the integrity of the clinical study and thus are important attributes to be included in the DP specifications. The appearance specification should note the external color and shape of the dosage form. A single discerning identification test is normally sufficient and may be derived from the HPLC test used for assay or impurities based on the comparison of the sample retention time or photodiode array spectrum to that of a comparator DS batch.

Assay: An assay specification of 90.0–110.0% is normally attainable and controllable for most tablet and capsule formulations used in early development and ensures dosage integrity and patient safety. Additionally, this acceptance criteria provides reasonable formulation process control while accounting for typical assay variability and formulation inconsistencies in early development given the higher levels of impurities/degradation products normally observed at this stage.

	Impurities and degradation products: Similar to the earlier proposal for DS, it is proposed that identification and qualification thresholds of three times those listed in ICH Q3B guideline (regardless of maximum daily dose), be applied for both impurities and degradation products in DP in the early stage. The proposed limit for unspecified individual degradation products in early development is NMT 1.0%. The limit of 5.0% for total degradation products in early phase DPs is higher than the corresponding limit of 3.0% for total impurities in DS due to the additional variability contributed by the formulation excipients, DP manufacturing process, and DP analytical methods.

	In early development, these limits are justified because clinical studies are of limited size and duration and stability information on early drug candidates with respect to sensitivities to moisture, hydrolysis, and oxidation is still being acquired. Later in development, process control, formulation design, and product protection strategies to minimize product degradation can be implemented after the compound sensitivities are better understood and thus tighter degradation product controls are justified.

	Uniformity of dosage units: The uniformity of active material in dosage units is important to the integrity of the clinical trial and to patient safety. The guidance for acceptance values is defined in 

General Chapter <905>. These acceptance criteria set a minimum standard for batch homogeneity and should be attainable at all stages of development for both capsules and tablets.

	Water content: As described for DS, a DP specification only needs to be established to control moisture levels in an investigational capsule or tablet dosage if the product quality or performance is known to be sensitive to water. As development progresses and additional knowledge is attained about product performance and stability in the presence of water, a specification may be applied, as necessary for release, shelf life, or both.

	Dissolution and disintegration: For rapidly dissolving immediate release formulations, it is recommended to include disintegration as a regulatory filed specification. Dissolution may be performed as an internal specification (i.e., report results without defined acceptance criteria) to gather product knowledge during early development (e.g., for poorly soluble drugs). As additional knowledge is gained toward establishing an 

 correlation (IVIVC), dissolution acceptance criteria should be established in later development (i.e., Phase 2b and beyond).

Other tests may be added to the DP specification as required. For example, residual solvents should be tested if solvents are used in the DP manufacturing process. Similar to DS, microbial testing may be considered, although a risk assessment may be performed to justify not including this test in the specification for solid oral dosage forms in early development.

	Some in-process control tests such as hardness and/or friability may have a critical impact on drug product quality (e.g., chewable tablets). In these cases, acceptance criteria should be included in the specification.

	A standard, risk-based approach has been presented for setting DS and DP specifications in early development for conventional solid oral dosage forms intended for US regulatory submissions. The recommendations herein are aimed at ensuring patient safety while allowing the flexibility to adapt to the frequent product and process changes that occur early in development. The authors' goal is to promote clarity and consensus within the pharmaceutical industry and to establish a more detailed approach to specifications in early development that are aligned across the industry and regulatory agencies. To further stimulate discussions on these approaches within the industry and with worldwide health authorities, this IQ working group is planning on conducting a workshop in the near future to promote robust debate and discussion on these proposed specifications in early development. In closing, it is recognized that each company needs to evaluate these early development recommendations based on the objectives of their individual drug development programs and may choose not to adopt this industry proposal on phase appropriate specifications.

works in Analytical Research and Development at Pfizer Inc. (Groton, CT); 

works in Analytical Chemistry at Merck & Co. Inc. (Rahway, NJ);

works in Analytical and QC at Kythera Biopharmaceuticals (Calabasas, CA); 

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

works in Quality & Records Management and 

 works in Analytical Development, both at Boehringer Ingelheim Pharmaceuticals Inc. (Ridgefield, CT);

works in Analytical Development at Biogen Idec (Cambridge, MA); 

 works in Analytical Development–Small Molecule at Millennium Pharmaceuticals, Inc. (Cambridge, MA); 

works in Analytical Research and Development at Amgen Inc. (Thousand Oaks, CA); 

works in Pharmaceutical Development at Teva Global Branded Products R&D (West Chester, PA); Peter Yehl works in Small Molecule Analytical Chemistry and Quality Control at Genentech (South San Francisco, CA); and 

 works in Process R&D, Global Pharmaceutical R&D at Abbott Laboratories (North Chicago, IL).

	*To whom all correspondence should be addressed.

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Guideline on the Limits of Genotoxic Impurities

Guideline on the Spec. Limits for Resid.of Metal Catal. or Metal Reagents 

IQ Consortium representatives explore and define common industry approaches and practices for applying GMPs in early development.