Jackson Pellett

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 quality-by-design principles that enable a manufacturer to limit and control the sources of process variability are equally important to measurement systems, because the variability in any process is partly made up of the contributions of the measurement system variability used to understand the process. The authors use real-life examples from drug development projects to outline how an understanding of chromatographic measurement system variability might be achieved.

The concept of quality by design (QbD) was introduced to the pharmaceutical industry in the International Conference on Harmonization (ICH) guidance documents, ICH Q8-Q11 (1-4), as a way to develop robust manufacturing processes for pharmaceutical products and substances. The aim of these documents is to describe a framework for developing a deeper understanding of how variability in the parameters of a manufacturing process can affect the quality of the final product.

In 2010, the European Federation of Pharmaceutical Industries and Associations (EFPIA) Subteam on Analytical Methods introduced the concept of applying QbD principles to analytical methods (5) where they described two main objectives: improved method performance and increased regulatory flexibility. As yet, no pharmaceutical regulatory standards (analaogous to ICH Q8-Q11) exist that describe how to apply QbD principles to analytical procedures. This article, therefore, focuses on how QbD tools may be used to obtain improved chromatographic method performance in such a way that is aligned with holistic drug product and substance control strategies (regulatory flexibility will not be addressed here).

 A QbD approach to understanding a measurement system such as a chromatographic method involves more than the demonstration of a depth of understanding regarding the choice of chromatographic separation parameters (e.g., through multifactor experimental design/robustness studies). Instead, to comprehensively follow QbD principles, the process should start with a statement of method design intent incorporating method performance characteristics focused on the minimum quality standard of the data the method must achieve so as to be fit for purpose. The foundation of a QbD method is, therefore, a fundamental understanding of the requirements of what the method needs to measure and the reliability requirements to which the method will be judged so as to produce data in compliance with a minimum quality standard. In other industries, the understanding of data “quality” is commonly communicated through an expression of the “uncertainty” associated with a measurement “result”. This uncertainty is treated with equivalent importance to the result itself (as it gives confidence in the quality of the measurement result and facilitates understanding in situations in which, for example, pass/fail criteria with respect to specification limits are being assessed). The concepts regarding how to express the uncertainty associated with a measurement data result can be found in many publications focused on measurement uncertainty (6-13).

In the pharmaceutical industry, the approach to understanding the uncertainty associated with measurement results is being addressed under analytical QbD principles. Here, the design of method performance characteristics is the foundation for ensuring measurement data quality can be rigorously controlled. In line with this, the EFPIA subteam introduced the concept of the analytical target profile (ATP) (5), which describes the performance characteristics of the method such that data the method produces will be “fit for purpose” (e.g., for making decisions about whether a batch of drug substance or drug product meets the specification criteria for assay or purity).

Once an ATP has been defined, a systematic process follows that includes a focus on design of the method (i.e., choice of technique and drafting of suitable starting conditions) followed by a full evaluation of the method using risk assessment tools and multifactorial experimental approaches. The final step focuses on an expression of the method conditions or ranges across which the ATP may be met, together with specific instructions to ensure adequate control of the method each time it is used. This process is holistically defined in the schematic in 


. It is important to note that it is not a one-time process but instead is an iterative one that should be revisited throughout the lifecycle of a method. Risk assessments or experiments performed against the ATP should be made each time any change to the product or process is made or new knowledge is gained.


As outlined previously, the first step in QbD method development is to define the ATP. There are at least three important components to be included in this statement:

The range for which the analytical method is expected to quantify the measurand (i.e., analyte)

The total uncertainty, expressed in terms of systematic (accuracy) and random (precision) uncertainty (i.e., variability) components

A description of the analyte to be tested, including the sample or matrix in which it will be tested.

Accompanying the second consideration, the level of risk should be understood for making incorrect decisions.

The following discussion outlines ATPs for a combined assay and purity method for a real-life drug substance, referred to henceforth as examplain hydrochloride (HCl):

Assay: The procedure must be able to accurately quantify examplain HCl drug substance over a range of 90% to 110% of the nominal concentration with accuracy and precision such that measurements fall within ±2.0% of the true value with at least a 95% probability. 

Purity: The procedure must be able to accurately quantify all related impurities relative to examplain HCl in the presence of drug substance and other impurities over a range from the reporting threshold through twice the specification limit. The accuracy and precision of the procedure must be such that the measurements fall within ±15% of the true value for impurity levels ≤ 0.15% with at least 90% probability and within ±10% of the true value for impurity levels > 0.15% with at least 90% probability.          

Justification of ATP statements. Assay ATP

. The ATP describes method performance requirements that define the risk of making an incorrect decision concerning the measurand (14). Analytical methods that adhere to the criterion stated in the ATP allow decisions (e.g., to accept or reject a batch based on the reported value) to be made based on a predefined, maximum level of risk, which is particularly important when the reported value is near the specification limit. For instance, a method that conforms to the assay ATP discussed previously will produce measurements for which there exists at least 95% confidence that these measurements reside within ± 2% of the true (unknown) measurand. That is, there is no more than a 5% chance of making an incorrect decision against the stated bounds of ± 2%.

Suppose a potency result of 100% label claim for a release test of a particular lot is measured. Further, suppose the analytical method used to obtain this result has been shown to conform to the ATP discussed previously. The risk that the true, unknown potency of the lot is below the specification limit of 98% is less than 5%, because the method conforms to the statement that at least 95% of measurements will reside within ± 2% of the true value. Consequently, there exists less than a 5% chance that the true unknown value differs by more than 2% from the observed measured value (95% confidence true value within 100% ± 2% or 98-102%).

The specification criteria for the assay is 98-102% label claim. It should be noted that the initial assay specification was 97.0-103.0%, and the ATP was established based on this orginal specification. The specification was subsequently tightened to 98.0-102.0% based on global regulatory feedback, and the original ATP was found to be fit for purpose with respect to the revised specification. The ATP criteria, as with ICH method validation criteria, are established based on considerations for patient safety and product quality and are consistent with the capability of analytical methodology used to characterize APIs. 

 illustrates pictorially the ATP as a probability contour plot (i.e., parabolic region in dark grey) for the examplain HCl drug substance assay as described. Here, the total uncertainty is comprised of precision (σ, random variability) and bias (μ, systematic variability). 

 also illustrates a rectangular region corresponding to the more generally applied acceptance criteria established for analytical measurements, in which bias and precision are defined independently. In this case, the rectangle represents the following method criteria: the measurement has no more than ± 2.0% bias and no more than 1.25% variability.

. First, the probability curve (parabolic region in dark grey) is contained within the more generally applied acceptance criteria (rectangular region in green). As such, the ATP criteria are slightly more restrictive. Second, when using the probability curve approach, method precision criteria (y-axis) is dependent on bias criteria (x-axis) and vice versa. This is because the total uncertainty, which is specified in the ATP, is a combination of these two components. Intuitively, a method with no bias can accommodate more variability (or lower precision) compared to a method with some non-negligible bias while providing the same total uncertainty. As method bias increases towards the ATP limit (±2 in 

), the required method variability decreases to zero to maintain the same analytical performance in terms of total uncertainty. When using the traditional approach of independent bias and precision assessments, there is no natural trade-off between those criteria, thus implying that a method may have both high bias and high variability (indicated by the yellow diamond in the upper right-hand corner of the green rectangle in 

), which could be problematic if not properly linked to the specification range. That is, a method operating at the yellow diamond (bias approximately + 2% and precision approximately 1.25%) does not maintain a 95% assurance that measurements will be within ± 2% of the true value. If the bias can not be corrected for, then measurements have only approximately a 50% chance of being within ± 2% of the true value. Even if this method is corrected for a known 2% bias (i.e., bias can be measured as different from random uncertainty), there exist < 90% probability that measurements will reside within a ± 2% range.

The expression for defining the acceptance region is shown in 

 where µ is true mean/accuracy (a parameter); σ is true sigma/precision (a parameter); e is allowable analytical window (a fixed constant); y is individual assay value (a random variable with mean µ and standard deviation σ); T is true analytical content (fixed target); p is minimum probability for individual assay to reside within error bound e (fixed constant); ϕ is normal density function centered at µ, with standard deviation σ.

Using Equation 1, the interplay between the appropriate analytical window (e), maximum sigma (σ), and minimum probability (p) can be probed for each unique analytical method.

. In this example, the specification criteria detail the limits for all related (specified) impurities to examplain HCl with specified impurities A and B both with limits of not more than 0.15%.

 illustrates the ATP as a probability contour plot for the examplain HCl drug substance impurities as described previously (i.e., parabolic region in dark grey). The total uncertainty is comprised of precision (σ, random variability) and bias (μ, systematic variability).

 also illustrates a rectangular region corresponding to the more generally applied acceptance criteria established for analytical measurements, where bias and precision are defined independently. In this case, the rectangle represents the following method criteria: the measurement has no more than ± 15.0% bias and no more than 10% variability. Here, the maximum allowable bias and precision is consistent with what can be expected for analytical procedure performance at these levels. For example, for levels ≤ 0.15% relative to examplain, the maximum allowable precision is 9.1% RSD and the maximum allowable bias is ± 15%.

There is a trade-off between precision and accuracy, such that it is not acceptable for the method to exhibit maximum bias and maximum variability concurrently, and, as with the assay ATP, the purity ATP criteria is slightly more restrictive when compared to the ICH validation criteria that would have typically been applied. From a practical perspective, the ATP criteria can be interpreted as follows: 9 out of 10 measurements will fall within 100% ± 15% of the true value, which corresponds to a range in which at least 9 out of 10 measured values will reside within 0.13% to 0.17%. This level of measurement uncertainty ensures patient safety. It is consistent with the philosophy of ICH Q3A (Impurities in New Drug Substances) as well as the current capability of contemporary analytical methodology used to quantitate low-level impurities in pharmaceutical drug substances. In fact, contemporary method capability was taken into consideration when the limits in ICH Q3A were established.

Analogous statements can be made for ATP criteria for impurities > 0.15% where the maximum allowable precision is 6.1% RSD and maximum allowable bias is ± 10%. This means that an impurity present at 0.3% (true value) corresponds to a range in which at least 9 out of 10 measured values will reside within 0.27%- 0.33% (i.e., true value ± 0.1 x true value). This tiered approach ensures that performance of the procedure is maintained for higher level impurities while ensuring patient safety and aligning with contemporary procedure capability.

. Once appropriate ATP criteria have been established, a technique should be selected. This selection depends not only on the match between measurement technique capability and ATP, but also on other scientific, practical, and business requirements. Typical considerations to bring to the discussion table between scientists who may be involved in using the method across the development lifecycle could include the physicochemical characteristics of the molecules in question, whether the method will be run in an R&D environment or a manufacturing environment, if on-line capability might be required, what sample turn-around times (from sampling to data reporting) are going to be necessary, and a plethora of other scientific and business-focused factors.

In the case examples discussed in this article, following such a discussion between R&D and receiving laboratory analytical scientists, reversed-phase high-performance liquid chromatography (RP-HPLC) was the method of choice.

 Once a technique has been chosen, a systematic process to arrive at “starting” or “draft” method conditions should be followed. In the case of RP-HPLC, the approach is shown in 

. Here, experimental studies are combined with in-silico modeling software to maximize the value of the results by being able to predict between experimental parameters (15, 16).

At the start of the process, it is essential to define the correct key predictive sample set (KPSS). For a pharmaceutical example, the KPSS available will be highly dependent on the drug-development lifecycle stage, and the ideal KPSS for an API  purity method should include all known process related impurities and known relevant potential degradants. If structures are known, then the experimental screening strategy may be supplemented by the information to be gleaned from a Log(P) vs. pH plot (P is the octanol water distribution coefficient of all analytes of interest). The column screening strategy employed in our laboratories and for the examples discussed here encompasses four stationary phases; two organic solvents; and acidic, neutral, and basic aqueous mobile phases (15). The primary objective of the screening is to obtain the most promising starting conditions with respect to overall selectivity, peak shape, and chemical stability, as well as minimal reliance on accurate pH control.

The next step is to investigate the combined effects of temperature and gradient profile using the starting conditions from the first phase of screening experiments (i.e., stationary phase, pH, and organic modifier). This experiment aims to explore the impact of various gradient profiles together with a range of temperatures across six experiments. The data obtained are modeled using software (e.g., ACD Labs LC Simulator), which allows the scientist to interpolate or extrapolate beyond the tested range to gain maximum value from a relatively low number of experiments. In the example, the data from the six experiments are used as the input for in silico optimization experiments. The result is a resolution map and optimized chromatogram within which the optimum conditions with respect to overall peak shape, resolution, and analysis time may be predicted (

The final stage of this systematic approach to method development is to check the effect of small changes in pH on the method performance. The pH is typically varied by up to +/- 1.0 pH units across five experiments (e.g., +1.0, +0.5, 0, -0.5, -1.0 pH units). Again, the data resulting from these experiments may be evaluated using software packages, such as the LC Simulator software, which allows for a more thorough understanding regarding the most suitable pH that will yield a more robust separation.

Experience with this systematic approach to method development indicates that approximately 75% of all applications lead to a successful (i.e., fit for purpose) method. In the remaining cases, various degrees of variations from the workflows have to be explored. For example, use of alternative buffer components, ion-pairing reagents, alternative column chemistries, and even completely different separation mechanisms can be applied.

 The risk-assessment exercise involves a systematic assessment of the draft method. The risk assessment process is designed to map individual method steps (e.g., standard and sample preparation or chromatographic separation) and identify method variables with the potential to affect method performance with respect to the ATP requirements. In the case described here, this exercise involved experienced analytical chemists from the method development and receiving laboratories and included those with some experience running the method. These participants were included to ensure that knowledge from previous studies were included and to understand differences in lab practices between the development and receiving laboratories. Three distinct focus areas were examined: (1) sample and standard preparation; (2) chromatographic separation; and (3) detection and data processing. Method variables were scored based on their potential to affect method performance together with the likelihood of occurrence using a cause-and-effect Matrix. Each variable was categorized as follows:

Experimental (X). Those that may vary and require further experimentation to understand (e.g., temperature, flow rate, mobile phase composition)

Controlled (C). Variables that can be controlled or specified at unique levels (e.g., column stationary-phase type and particle size, column diameter, length, and supplier)

Noise (N). Those that cannot be controlled or are allowed to vary randomly from a specific population (e.g., column age).

Method variables with the highest scores (i.e., combined high probability and high impact on chromatographic performance relative to the ATP) were further assessed by way of multifactor experimentation. An example of the multifactor experimentation from the chromatographic separation focus area follows.

 Two separate design-of-experiments (DoE) studies were performed to identify and verify the optimum method conditions. The first DoE was conducted to explore and identify a preliminary set of chromatographic conditions for further verification. The second DoE was conducted to verify conformance of the method to the ATP criteria.

 represents the experimental region from the first wave of experimental design studies (DoE-1). This design included the following parameters which were identified during the risk assessment as having the highest potential to influence the chromatographic separation: flow rate, trifluoroacetic acid (TFA) content in mobile phase, column temperature, gradient change, and start and end times. A preliminary set of suitable operating conditions was identified by assessing the chromatographic performance measured during DoE-1 against the predefined criteria shown in 

The results of DoE-1 were used to identify the variables that may affect chromatographic performance. Statistically significant effects at the commonly-accepted 0.05 level of statistical significance were determined using Student’s critical t-values. Statistical models of these results were developed for each method attribute and used to define the variable ranges over which the method is expected to meet the predefined criteria in 

. These ranges of chromatographic variables defined a preliminary experimental design space referred to as the method operable design region (MODR).

Critical   pair resolution (impurity A: impurity B)

Relative   standard deviation (RSD) at limit of quantitation (LOQ): (impurity A at 0.05%   LOQ)

Examplain   hydrochlodride retention time

A subsequent experimental design study (DoE-2) was executed to verify that the method complied with the criteria specified in the ATP. Verification testing was performed using experimental conditions spanning the preliminary predicted MODR identified from DoE-1 results. Based on the data analyses from DoE-1, the three parameters that had the largest collective impact on both resolution and limit of quantitation (LOQ) were the gradient change time, the column temperature, and the mobile phase TFA concentration. To select the method conditions, a standard 23-1 design was chosen that spanned a predicted acceptable range of method performance. Specifically, the gradient start time was varied between 15-19 minutes, the column temperature between 25-32 C, and TFA content between 0.04-0.06%. The other parameters that had an impact on method performance were flow rate and gradient start time. For this experiment, however, those levels were fixed at values that would stress the system in terms of performance; that is, at levels nearing the predefined criteria. Flow rate was set at 1.05 mL/min and gradient start time at 0.5 minutes. Gradient end time did not affect method performance. Testing was conducted over four days, by two analysts, in two different laboratories (development and testing labs) using HPLC systems from two vendors (Agilent and Shimadzu).

The chromatographic variables used to verify the MODR are shown in 

. Verification testing was initially performed using conditions 1-4. 

 show how results using conditions 1, 3, and 4 all met ATP criteria. Results generated using condition 2, however, failed to adequately meet ATP criteria due to insufficient resolution (Rs < 1.0) for the critical pair. This is illustrated in

 where condition 2 is clearly within the red shaded region. As a result of this failure, the MODR model was refined, and a new combination of verification variables, condition 5, was added.

In lieu of preparing separate solutions, injection volumes of 9, 10, and 11 µL were used to verify conformance to the ATP over the range of 90-110% of the nominal injection concentration. The flow rate was held at 1.05 mL/min for the original verification study (conditions 1--4), as a flow rate slightly above the 1.0 mL/minute target was considered a worst case scenario based on the results from DoE-1. The flow rate was changed to 1.00 mL/min (the target condition) for condition 5. The final verified MODR incorporating verification condition 5 is illustrated in 

As a means of visualising how these results from both labs during DoE-2 comply with the ATP, 

 shows the probability contour plot (using 

) illustrating method variability (σ≈relative standard deviation or RSD) vs. calculated bias/process acceptance criteria (98-102% potency). The grey-shaded region is the graphical representation of the ATP criteria for the assay method. Each point represents 24 replicates at each of the five MODR verification parameters run in the two different labs. This graph illustrates minimal (statistically insignificant) bias relative to the proposed 98.0-102.0% assay acceptance criteria. Although slightly greater variability was observed for Lab 2 results, all results fall within the ATP for the assay method (grey region). The triangular regions surrounding each point represent the simultaneous 95% confidence interval for accuracy and precision for each of the points as described in Lindgren’s Statistical Theory (14).

Similarily, the probability contour plots in 

 illustrate method variability (σ≈ RSD) vs. calculated bias/process acceptance criteria for results generated from both laboratories for impurity A at > 0.15% and impurity B at ≤ 0.15%, respectively. Each point represents 24 replicates at each of the five DoE conditions run in the two different labs. The simultaneous 95% confidence interval for accuracy and precision is also shown on the plots. These results illustrate how impurity A and B quantitation data meets the ATP criteria for quantitation of impurities in that > 90% of data are within ± 10% of expected normalized value for values > 0.15%, and > 90% are within ±15% of the expected normalized value for values ≤ 0.15%.

Based on the statistical modelling from DoE-1 and DoE-2, the entire white region in 

 is predicted to be capable of meeting the ATP acceptance criteria. For operator simplicity, however, the operating ranges were constrained to the ranges listed in 

The quality-by-design principles used to control process variability are equally important to measurement systems because process variability includes contributions from measurement system variability. The authors use real-life examples from drug development projects to outline how an understanding of chromatographic measurement system variability might be achieved.

Using Quality by Design to Develop Robust Chromatographic Methods

	The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ) formed in 2010, and is an association of more than 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 P

, a paper 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 1 through Phase 2a) (1). A consequence of the absence of clarity surrounding early phase GMP guidances has been varied interpretation and application of existing GMP guidances within different companies according to its 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 mostly relevant to commercial product development and do not distinguish differences in requirements between early development and later stage development (Phase 2b and beyond). A key driver of this working group (WG), therefore, has been to collectively define the minimum acceptable practices within the industry regarding GMP expectations in early development that allow for added flexibility, are consistent with existing guidance and statutes, and which assure product quality and patient safety (2–4).

	The second paper in this series addressed recommendations for analytical method validation of both drug substances (DS) and drug products (DP) (5). In this third article of the series, the authors address the application of GMPs in early development as they pertain to drug-product manufacturing.

	As noted previously in the introduction to the paper series, due to high attrition in early development, most companies try to minimize the resource required to advance compounds into human clinical trials by employing simple formulations and manufacturing processes (1). For example, drug substance filled in bottle, drug in capsule, or simple powder blends filled in capsule are frequently used. Even for more challenging molecules, for example, those with low aqueous solubility, prototype formulations designed to investigate bioavailability enhancement (e.g., amorphous solid dispersions, lipid-based drug delivery systems, nanosuspensions) are evaluated in as simple a manner as possible. For example, on-site preparation at the clinic site of an amorphous solid dispersion by weighing into a capsule, or by suspension in a suitable vehicle may be utilized instead of a finished tablet or capsule dosage form. Whatever approach to formulation/process is taken, there is a need for flexibility in manufacturing due to limited product and process understanding in early development.

Based on the collective industry experience of the members of this working group, the authors believe that pharmaceutical companies could be making better use of available guidances as they pertain to drug-product manufacturing in early development. This belief was reflected by the mixed responses to a survey of IQ member companies conducted in late 2011 (see 

). Accordingly, in this article, the authors provide pragmatic recommendations related to GMP drug-product manufacturing focusing on those areas where it is believed there is opportunity for added clarity and flexibility, without added risk to product quality and patient safety.

	Following a brief explanation of the role and importance of quality systems, the areas highlighted in this paper include facilities, equipment, materials (receipt and approval for use), and batch documentation. Not covered is cleaning verification/validation, as this is a topic that is addressed in detail in the industry (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 position, it is recognized that each company needs to evaluate these recommendations for drug-product manufacturing practices based on individual business needs and risk culture.

In early development, relationships between material attributes, process parameters and product quality attributes are typically not well understood. It should be anticipated that even during GMP manufacture, there will likely be a need to deviate from the process conditions specified in a batch record. Quality systems should have the flexibility to allow these changes to be documented in batch records without formal prior approval from the Quality department. However, these changes should be reviewed by Quality after production, to assess the potential impact to product quality and patient safety. It is crucial to summarize and track process changes because much of this information will be used to develop process understanding and may be included in development history reports. In a similar manner, unplanned deviations from the written manufacturing procedures should be documented and justified, but may not need to be addressed in a formal corrective and preventive action (CAPA) system, because the process is changing continuously as part of the development process. Unplanned deviations that are likely to impact product quality and patient safety, such as cleaning failures, contaminations, and certain equipment failures must be investigated and corrective actions put in place to prevent recurrence.

 To assist in the application of risk-based decision making in the development and manufacturing of drug product, the authors recommend that companies apply a scientific and risk-based approach, similar in principle to that of the ICH Q9 

guideline (7). Annex I of the guideline describes various methods and tools that can be useful to determine the relative risks related to system risks, such as facility and people; organizations (including quality systems); process risks and product risks (safety and efficacy). There are many ways of identifying, qualifying, and mitigating operational and quality risks. Regardless of the methodology used, a documented strategy and good records of risk-based decisions are important in ensuring that the appropriate factors are considered for the protection of patients and product quality.

	Regardless of the scale of manufacturing, the facility used for manufacturing clinical trial supplies must meet the basic GMP requirements as described in the regulations and guidance documents. Below are three scenarios for early development and the advantages of each as pertaining to early development. The first involves a pilot plant facility designed and equipped for routine GMP operations. The second scenario aims to establish a GMP area within a laboratory environment. The third example focuses on conducting GMP manufacturing or leveraging the practice of pharmacy in close proximity to the clinical site.

GMP facility for drug-product manufacture. 

The traditional approach in GMP drug-product manufacture is to use a dedicated facility (often called a pilot plant) for early phase clinical trials. Advantages of this approach include that the quality systems for the facility (i.e., maintenance, calibration, cleaning, change management, CAPA, and documentation) are well defined, and that training and other activities required for maintaining GMP compliance are centralized. Other drivers to use a pilot plant in early development may be the need for specialized equipment, or larger batch sizes in special situations.

In some cases, it may be advantageous to establish a GMP area within a "laboratory setting" (i.e., a drug-development facility not dedicated to the production of clinical supplies) for the manufacture of drug product in early development. The rationale for this approach might be to avoid the significant investment in setting up a dedicated facility and to create simpler, more flexible systems that meet GMP requirements but are tailored for the specific activity envisioned. Examples where this approach might be considered include the need for special containment not available in the pilot-plant; the need to work with radioactive or hazardous materials, use of controlled substances and the production of "one-off manufactured" product used for proof of concept. The business rationale should be documented and approved by the manufacturing and Quality groups. As long as the appropriate GMP controls are maintained, especially as related to operator safety, cleaning, and prevention of cross-contamination, there is no compliance barrier to using "lab-type" facilities for the manufacturing of early phase clinical batches. Before GMP manufacturing is initiated, however, a risk assessment should be conducted and documented. Inclusion of representatives from Quality, analytical, clinical manufacturing, product development, and environmental health and safety would be prudent. When selecting/designing an early development clinical manufacturing facility, consideration should be made for the receipt, storage, dispensing, and movement of materials. The manufacturing processes in the nondedicated area must protect the product, patient, and the manufacturing operators.

	Additionally, companies should consider what items are appropriate for the manufacture. For example, the use of a certified laminar flow hood may be a better choice for manufacturing than a fume hood, because the former is designed to prevent contamination of the product, protect the operator, and the laboratory environment. In addition, with the appropriate cleaning, a laminar flow hood can more easily be used for multiple products. Small scale/manual equipment or procedures may be the best approach because the space is likely to be limited. With a small batch size, the use of small scale or manual equipment/procedures will minimize yield loss. Additional measures to be assessed include appropriate gowning and operator personal protection devices, area and operator monitoring for potent or radiolabeled drug exposure, and so forth.

	Documentation of the facility preparation, product manufacture, and the return of the facility to the previous state, if needed, is recommended. This documentation should describe the rationale for the manufacture in the nondedicated area, risk assessment, preparation of the area, cleaning procedures, and list of responsible persons. This documentation can reference existing procedures or standard operating procedures (SOPs) along with documents associated with the meetings and preparation for the manufacture of the batch. Batch records and cleaning records should be part of the documentation and should follow the company's data-retention policy.

On-site preparation of formulations, sometimes referred to as "extemporaneous preparation" or "compounding," is not considered manufacturing, but is an effective method to prepare early clinical supplies using the local laws governing the practice of pharmacy. The processes used for on-site preparation can be as simple as preparing and diluting solutions or filling capsules with API to more complicated processes such as blending and compression of tablets. An IQ working group addressing current practices in extemporaneous preparation has conducted a survey to be communicated at a later date, which confirms that only a few companies have adopted practices to take advantage of more advanced formulation approaches at the clinic site (8). This is a missed opportunity, because on-site preparation of formulations has the potential to dramatically speed industry's ability to answer critical questions related to pharmacokinetic parameters, absolute or relative bioavailability, feasibility of extended release and bioavailability enhancement approaches for difficult to deliver molecules. Currently, each company must develop its own best practices to assure product quality and patient safety; often, these practices are based on compendial or professional association publications (9–11). The authors believe this topic warrants further discussion between the industry and regulatory authorities to determine when dose preparation at the clinical site is appropriate and the level of quality controls required. The results of such a discussion could help to increase the utilization of on-site preparation of clinical trial materials to facilitate quick answers to critical questions in early drug development and ultimately bring the best possible products to patients in the shortest time.

Most equipment used to manufacture early GMP drug product is be managed under a qualification, preventive maintenance, and calibration program for the GMP facility. However, in early development, there may occasionally be a need to use equipment that is not part of such a program. Rather than performing a comprehensive qualification for a piece of equipment not expected to be frequently used, an organization may choose to qualify it for a single step or campaign. Documentation from an installation qualification/operational qualification (IQ/OQ) and or performance verification at the proposed operating condition is sufficient. For example, if solution preparation needs a mixer with a rotation speed of 75 rpm, then documentation in the batch record using a calibrated tachometer to verify that the mixer was operating at 75 rpm will suffice.

	The use of dedicated or disposable equipment or product contact parts may be preferable to following standard cleaning procedures to ensure equipment is clean and acceptable for use. However, not all equipment or equipment parts are disposable or may have a substantial cost that makes disposal prohibitive. In that case, the product contact parts could be dedicated to a specific drug substance for use in drug product manufacture. Dedicating product contact parts to a compound may be costly and may be avoided in some cases by carefully considering product changeover and effective cleaning methods when purchasing equipment.

	Another item to consider with respect to equipment, is that the more complicated the equipment is to run or maintain, the less desirable it might be for early GMP batches. In most cases, simple equipment is adequate and will uses less material and consume less total time for preparation, operation, and cleaning activities.

Part 211.42 state that buildings or areas used in the receiving, storage, and handling of raw materials should be of suitable size, construction and location to allow for the proper cleaning, maintenance, and operation (7). The common theme for this section of 

 Parts 210 and 211 is the prevention of errors and contamination. In principle, the requirements for buildings and facilities used in early phase manufacturing are not significantly different than those for later phases or even commercial production. However, there are some areas that are unique to early clinical trial manufacturing.

 regulations under Part 211.80 provide good direction with respect to lot identification, inventory, receipt, storage, and destruction of materials (7). The clear intent is to ensure patient safety by establishing controls that prevent errors or cross-contamination and ensure traceability of components from receipt through clinical use. In general, the requirements for the control of materials are identical across all phases of development, so it is important to consider these requirements when designing a GMP facility within a laboratory setting.

	For example, all materials must be assigned a unique lot number and have proper labeling. An inventory system must provide for tracking each lot of each component with a record for each use. Upon receipt, each lot should be visually examined for appropriate labeling and for evidence of tampering or contamination. Materials should be placed into quarantine or in the approved area or reject area with proper labeling to identify the material and prevent mix-ups with other materials in the storage area. Provision should be made for materials with special storage requirements (e.g., refrigeration, high security). The storage labeling should match the actual conditions that the material is being stored and should include expiry/retest dates for approved materials. Although such labeling is inconvenient for new materials where the expiration or retest date may change as more information is known, this enables personnel to be able to determine quickly whether a particular lot of a material is nearing or exceeding the expiration or retest date. General expiry/retest dates for common materials should be based on manufacturer's recommendation or the literature.

	Finally, there are clear regulatory and environmental requirements for the destruction of expired or rejected materials. It is important to observe regional and international requirements regarding the use of animal sourced materials (12). It is recommended to use materials that are not animal sourced and that there be available certification by the raw material manufacturers that they contain no animal sourced materials. If animal sourced raw materials must be used, then certifications by the raw material manufacturers that they either originate from certified and approved (by regulatory bodies) sources for use in human pharmaceuticals, or that the material has been tested to the level required for acceptance by regulatory agencies (following US, EU, or Japanese guidelines, as applicable) is required.

It is a GMP requirement that all raw materials for the manufacture of drug product have appropriate specifications to ensure quality. The compendial requirements should be used for setting specifications provided the material is listed in at least one pharmaceutical compendium (e.g., 

). It is important that the use of materials meeting the requirements of a single compendium is acceptable for use in early phase clinical studies conducted in the US, Europe, and Japan. For example, a material that meets 

 criteria and is used in the manufacture of a drug product should be acceptable for use in early clinical studies in the European Union. In the absence of a pharmaceutical compendium monograph, the vendor specification and/or alternative compendial specifications such as USP's Food Chemical Codex should guide specification setting. In any case, the sponsor is responsible for the establishment of appropriate specifications. Therefore, it is the authors' position that good practice is to have at least a basic understanding of the manufacture, chemistry, and toxicology of the materials to guide appropriate specification setting.

The minimum testing required for incoming materials is visual inspection and identification. However, as mentioned above, the appropriate tests should be determined for the material based on the knowledge of the manufacture, chemistry, and toxicology. If the vendor is qualified, then the certificate of analysis may be acceptable in conjunction with the visual inspection and identification testing (see "Vendor Qualification" section below).

Ideally, manufacture of a bulk drug product should begin with approved material specifications and with materials that are fully tested and released. However, there are circumstances where it may not be feasible to start manufacture with approved specifications and fully tested and released materials, including API. Manufacturing prior to final release (sometimes called manufacturing "at risk") may be acceptable, however, because the quality system ensures that all specifications are approved, test results are within specifications, and all relevant documents are in place before the product is released for administration to humans. The "risk" must lie fully with the manufacturer and not with the patient.

Vendors supplying excipients, raw materials, or API must be qualified by the sponsor. Appropriate qualification should depend on the stage of development and an internal risk assessment. For, example if a vendor has a history of supplying the pharmaceutical industry and the material is to be used in early development, a paper assessment (e.g., a questionnaire) should be sufficient. If a supplier does not have a history of supplying the pharmaceutical industry, a risk assessment should be performed and depending on the outcome a site audit may be required prior to accepting material for use.

	Ideally, vendors should be qualified prior to using raw materials for manufacture. However, it is acceptable for qualification to proceed in parallel as long as documentation/risk assessments are available prior to product release and as in the previous section all risk lies with the manufacturer and not the patient.

Batch record documentation preparation. 

Manufacturing documentation is a basic requirement for all phases of clinical development. 21 

 Parts 211.186 and 211.188 describe master production and batch production records, respectively (7). The stated purpose of the master production record is to "assure uniformity from batch to batch." Although the record assurance is important for a commercial validated manufacturing process, it does not necessarily apply to clinical-development batches. Material properties, manufacturing scale, and quality target product profile frequently change from batch to batch. Therefore, batch production records are the appropriate documentation for clinical trial supplies. Batch production records for Phase 1 materials should minimally include:

		Name, strength, and description of the dosage form

		A complete list of active and inactive ingredients, including weight or measure per dosage unit and total weight or measure per unit

		Theoretical batch size (number of units)

		Manufacturing and control instructions.

	These minimum requirements are consistent with the FDA 

Guidance for Industry: cGMP for Early Phase Investigational Drugs, 

which requires a record of manufacturing that details the materials, equipment, procedures used and any problems encountered during manufacturing (2). The records should allow for the replication of the process. On this basis, there is flexibility in the manner for which documentation of batch activities can occur, provided that the documentation allows for the post execution review by the quality unit and for the retention of these records.

Review and approval of executed batch records by the Quality unit is required per 21 

 Part 211.192 (7). This review and approval is required for all stages of clinical manufacturing. Pre-approvals of batch records should be governed by internal procedures as there is no requirement in 

 21 that the Quality unit pre-approves the batch record (though this is highly recommended in order to minimize the chance of errors). Indeed, 

shows that pre-approval of batch records by the Quality Unit is practiced by all 10 companies that participated in the IQ Consortium's drug-product manufacturing survey related to early development. Batch records must be retained for at least 1 year after the expiration of the batch according to CFR Part 211.180, but many companies keep their GMP records archived for longer terms.

 Part 211.130 requires inspection of packaging and labeling facilities immediately before use to ensure that all drug products from previous operations have been removed. This inspection should be documented and can be performed by any qualified individual.

	Although line clearance for bulk manufacture is not specifically mentioned in the 

, it is expected that a room clearance be performed. At a minimum, this clearance should be performed prior to the initiation of a new batch (i.e., prior to batch materials entering a processing room).

During the early stages of development, final dosage form release testing confirms product quality and support establishment of hold times later in the clinical development. There is no requirement to establish hold times for work in process in early development. Specific formulation and stability experience, which is usually limited at this stage of development, should be leveraged to assess any substantial variations from expected batch processing times. The data gathered from these batches and subsequent development can be used to help establish hold times for future batches. (Exceptions to this approach may include solution or suspension preparations used in solid dosage form manufacturing, where procedures typically govern allowable hold times to ensure the absence of microbial contamination in the final product.)

Changes to raw materials, processes, and products during early development are inevitable. It is not required that these changes be controlled by a central system but rather may be appropriately documented in technical reports and manufacturing batch records. Any changes in manufacturing process from a previous batch should be captured as part of the batch record documentation and communicated to affected areas. The rationale for these changes should also be documented as this serves as a source for development history reports and for updating regulatory filings. The authors recommend that those changes that could affect a regulatory filing be captured in a formal system.

Process parameters should be recorded but do not need to be predetermined because processes may not be fixed or established in early development. Given the limited API availability in early development, a clinical batch is often the first time a product is manufactured at a particular scale or using a particular process train. Therefore, process changes should be expected. Process trains and operating parameters must be documented in the batch record but changes should not trigger an exception report or CAPA. Changes should be documented as an operational note or modification to the batch record in real time. Such changes driven by technical observations should not require prior approval by the Quality unit, but should have the appropriate scientific justification (

 formulator/scientist) or the appropriate flexibility built into the batch record to allow for the changes. This documentation should be available for Quality review prior to product disposition.

Actual yields should be calculated for major processing steps to further process understanding and enable optimization of processes. Expected yield tolerances are not always applicable to early development manufacture. At this stage of early development, when formulation and process knowledge is extremely limited, there may be no technical basis for setting yield tolerances and, therefore, this yield may not be an indicator of the quality of the final product.

In-process tests and controls should follow basic requirements of GMPS to document consistency of the batch. For capsule products, these requirements may include capsule weights and physical inspection. For tablet products, compression force or tablet hardness and weights should be monitored together with appearance. R&D sampling, defined as samples taken for purposes of furthering process understanding but not utilized for batch disposition decisions, is a normal part of all phases of clinical manufacturing. In early development manufacturing, a sampling plan is required for in-process control tests, but not for R&D samples. However, for the purpose of material accountability, R&D sampling should be documented as part of batch execution. For these samples, testing results may be managed separately, and are not required to be included in regulatory documentation.

	Organizations involved in manufacture of Phase 1 and 2a clinical supplies should recognize that process understanding is very limited in early development. Quality systems must be robust enough to ensure patient safety, but should also be flexible enough to accommodate accelerated timelines and process changes in real time. The special needs of small scale GMP manufacturing should also be considered when designing facilities, purchasing equipment, and selecting the type of dosage forms to use in early clinical studies. Companies are encouraged to apply quality risk management principles to support these risk-based decisions.

	The authors also believe that underutilized approaches exist (e.g., on-site preparation of more complex dosage forms) for quickly and efficiently answering formulation related questions about bioavailability, pharmacokinetics, and target release rates for controlled-release formulations. The potential benefits and risks of these approaches warrant further discussion. Finally, documentation of manufacturing operations should be risk-based. Manufacturing instructions in early development should not be overly prescriptive as to restrict process changes or discourage sampling for further process understanding. Changes should be expected, and able to be quickly reviewed and approved by the Quality department, or a qualified delegate.

	To further stimulate discussions on these approaches within the industry and with worldwide health authorities, the IQ Consortium's GMPs in Early Development Working Group is planning on conducting a workshop in the near future to promote robust debate and discussion on these recommended approaches to GMPs in early development. The group strongly believes that such dialogue will improve alignment between development, quality assurance, and chemistry/manufacturing/controls (CMC) regulatory groups within the pharmaceutical industry. In addition, agreement between the industry and drug regulatory authorities regarding acceptable approaches to applying GMPs in early phases of drug development would allow for a more nimble and flexible approach in early development, while still providing appropriate controls to ensure patient safety.

 is in pharmaceutical development at AstraZeneca (Wilmington, DE); 

is in pharmaceutical development at Vertex Pharmaceuticals (Cambridge, MA); 

 is in quality at ARIAD Pharmaceuticals (Cambridge, MA); 

is in pharmaceutical sciences and clinical supply at Merck (Summit, NJ); 

 is in pharmaceutical sciences at Pfizer (Groton, CT); 

is in small molecule pharmaceutical sciences at Genentech (South San Francisco, CA); and 

 are in drug product development at Abbott Laboratories (Abbott Park, IL).

	*To whom all correspondence should be addressed.

Guidance for Industry: CGMP for Phase 1 Investigational Drugs 

(Rockville, MD, July 2008).
	3. FDA, "Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials," 

Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use,

 Annex 13: Investigational Medicinal Products (Feb. 2010).
	5. D. Chambers, 

 (7) 76–84 (2012).
	6. D.A. LeBlanc, in "Validated Cleaning Technologies for Pharmaceutical Manufacturing," (Interpharm/CRC, Washington, DC, 2000).
	7. 

, Title 21, Food and Drugs (Government Printing Office, Washington, DC).
	8. Personal communication with Mike Kress, Leader, IQ Consortium Drug Product Working Group on Extemporaneous Formulations (May 2012).
	9. 

 30 General Chapter <795> Pharmaceutical Compounding-Nonsterile Preparation, 344–350.
	10. 

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