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

geopaul/E+/getty images The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically driven standards and regulations for pharmaceutical and biotechnology products worldwide.  In previous issues of Pharmaceutical Technology, papers written by the IQ Consortium’s GMPs in Early Development Working Group described the desire and rationale for more clear and consolidated recommendations for GMPs in early development (Phase I through Phase IIa) (1-5). 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:

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  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.


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  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.


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  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.

Acknowledgements

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.

References

1. A. Eylath et al., Pharm. Technol. 36 (6) 54-58 (2012).
2. D. Chambers et al., Pharm. Technol. 36 (7) 76-84 (2012).
3. R. Creekmore et al., Pharm. Technol. 36 (8) 56-61 (2012).
4. B. Acken et al., Pharm. Technol. 36 (9) 64-70 (2012).
5. M. Coutant et al., Pharm. Technol. 36 (10) 86-94 (2012).
6. www.iqconsortium.org
7. FDA, Guidance for Industry: cGMP for Phase 1 Investigational Drugs (CDER, July 2008).

About the Authors

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

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Downstream Processing: A Revalidation Study of Viral Clearance in the Purification of Monoclonal Antibody CB.Hep-1

ABSTRACT

This article revalidates the effectiveness of affinity chromatography, matrix sanitization, and storage procedures used in monoclonal antibody CB.Hep-1 purification to remove and inactivate viruses after process scale-up. The scale up of the CB.Hep-1 purification process demonstrated a similar removal factor for enveloped and nonenveloped viruses compared to the initial validation study. The HSV-1, HIV-1, and CPV viruses were sensitive to incubation with ethanol at 70% concentration (3.0–4.6 Logs). We found that 0.1N HCl is a robust chemical agent able to inactivate >6.13 Logs of nonenveloped high resistance viruses while ethanol at 20% concentration inactivated 3.7 Logs of enveloped viruses HSV-1 and HIV-1 but was unable to inactivate nonenveloped viruses HPV-1 and CPV.

Monoclonal antibodies (MAbs) are employed as immunoligands in the purification processes of biopharmaceutical products.^1,2 Virus transmission poses a high potential risk for patients who must be treated with these biopharmaceuticals, if MAbs come from human or animal sources.^3,4 It is necessary to validate the purification process capacity to remove and inactivate any potential viral contaminant.^5,6
Regardless of extreme virus controls, several instances of biological contamination have occurred. Research on virus contamination sources have shown that viruses can be introduced into the manufacturing process in different ways, illustrating the importance of viral clearance studies to guarantee the biopharmaceutical product safety.⁷

Acronym List

Validation of the purification method plays an essential role in establishing biological product safety, especially when there is a high risk for the source to be contaminated with known human pathogenic viruses. Since several contamination instances have occurred with agents whose presence was not known, validation also provides a high degree of confidence that these agents may also be removed.⁸

FDA defines validation as, "Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes".⁹ The rationale is that if more effort is placed on validation at the beginning, then there will be less chance for failure during product life.¹⁰

Validation studies for purifications proceses involve the deliberate addition of a virus to one or more purification steps to measure the extent of its removal and inactivation capacity. It is not necessary to validate all purification steps, but only those that could contribute to virus removal or inactivation. To prevent the deliberate introduction of viruses into the manufacturing process, the validation studies should be done in a separate facility and in a scaled-down version of the manufacturing process. Validation at the small scale is an efficient way to perform viral clearance validation studies.¹¹

GENERAL PROCEDURE FOR VALIDATION

CB.Hep-1 MAb is a mouse IgG-2b, specific for HbsAg.¹² This MAb is used as an immunoligand in the antigen-purification process, which is one step in the manufacturing of the Hepatitis B vaccine for human use.^13,14 The main aim of our work was to investigate if the affinity chromatography used routinely in the purification of CB.Hep-1 shows the same virus removal factor after a scale-up process. We measured the virus inactivation factor of the column sanitization protocol using 70% ethanol and the matrix storage conditions in 20% ethanol. We also evaluated the column sanitization protocol with 0.1 N HCl to increase the inactivation factor for high resistance non-enveloped viruses.

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Validating Analytical Methods for Biopharmaceuticals, Part 1: Development and Optimization

Regulatory guidance documents are written by committees, resulting in statements that are both exact and generic. Meeting regulatory requirements involves not only interpreting these documents correctly but also addressing their omissions. This article provides practical guidance on issues that are not thoroughly covered by current guidance documents regarding validation of analytical methods for biopharmaceuticals.

Figure 1: Process Map of Analytical Method Development and Validation

Four of the key regulatory guidance documents on methods validation state, "Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use."^1-4 We have all read, and likely used, this phrase many times when summarizing method-validation results. However, according to Muire-Sluis, development scientists often point out that "validated methods may not be valid."⁵ The question therefore arises, what exactly makes a validated method valid? According to CBER, "the acceptability of analytical data corresponds directly to the criteria used to validate the method."⁴

We can generate evidence for the validity of analytical data in the formal method-validation program where all critical parameters are extensively tested under a detailed protocol that includes scientifically justified and logical step-by-step experimental approaches. All planned data sets must fall within pre-established protocol acceptance criteria (limits). These criteria should be derived from and justified in relation to historical data and product specifications. Once evidence for all critical elements is provided, the validated method will become the official, licensed procedure for that particular product and process step, and it will then support production and product release. The relationship between "valid" or "suitable and validated" is often overlooked, but there is a high price when "validated" test systems are simply inappropriate.

Incentives to replace existing licensed test procedures may come from regulatory agencies, or they could be motivated by potential cost savings, ease of use (automation), and the opportunity to generate more accurate and reliable results.

The International Conference on Harmonisation (ICH)'s Q2A and Q2B^1,2 and the United States Pharmacopoeia's USP 27 <1225>⁶ should be used for basic guidance. However, following just these guidelines will not necessarily produce a "valid" method and may not provide sufficient evidence that this method is suitable for product release. FDA provides guidance on some of the scientific issues that are not covered by Q2A and Q2B or USP 27.^3,4,6

Process Map. A process map showing the recommended steps for the selection, development, validation, and potential transfer of analytical methods, illustrating all functional responsibilities was developed. Frequently, larger companies have separate functional units for method development, validation, and testing. The process flow in Figure 1 describes an ideal sequence of steps for better analytical method validation (AMV).

The rigorous standards suggested here are ideal, but they are not necessarily required or followed during method development. Methods can be developed without strict adherence to GMP regulations if adequate documentation systems are used.

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FDA's Draft Guidance for Process Validation: Can It Be Applied Universally?

In November 2008, the US Food and Drug Administration issued Draft Guidance for Industry—Process Validation: General Principles and Practices (1). The guidance outlines regulatory expectations for process validation following a "life-cycle concept" that describes a "cradle-to-grave" approach for validating pharmaceutical processes (2). The life-cycle approach builds upon the results of experimental activities during development to define operating parameters and product specifications that are used in initial and ongoing process qualification. The life-cycle concept provides a robust means for the development, manufacture, and control of pharmaceutical products.

The guidance document covers validation largely at a conceptual level and avoids narrow precepts and specific examples. This approach is appropriate because the document addresses the subject from active pharmaceutical ingredient (API) production (by either chemical synthesis or biological processes) through drug-product production for all pharmaceutical dosage forms. The intended breadth of coverage embraces a myriad of unit operations in the preparation and manufacture of these products. Unstated is whether the draft guidance is intended to be applied to supportive processes that are not an inherent part of the formulation process. Among the support processes are cleaning, inspection, sterilization, and aseptic processing. Each of these processes can be an essential part of pharmaceutical manufacture that requires validation.

Basics of the draft guidance

The draft guidance recommends a defined and structured approach for process-validation activities within an organization. During the design and development stage, experiments should define the relationship between the independent process parameters and the dependent product attributes. These studies should be conducted in a predefined manner, and the results should be documented for later reference. The goal of process development is the attainment of knowledge regarding the process–product relationships to support later commercial production. The greater the knowledge accumulated at this early period, the more assurance the firm will have that it can successfully launch and maintain the process at a commercial scale. From a compliance perspective, this approach makes excellent sense; the knowledge gained during preclinical and clinical-stage experimentation provides a way to link clinical data obtained at the smaller scales with data from the later production process. A well-developed process is one for which the critical process parameters have been identified and control ranges for each have been established (3). The development experiments should evaluate the interaction between the independent and dependent variables until the results of the process are predictable and routinely acceptable. Multifactorial experiments can assess the relationships between the variables and build knowledge about the process's limitations. The experiments performed at a smaller scale establish the acceptable ranges for the various independent process parameters. Thus, when the process is operated under the appropriate conditions, operators have substantially greater confidence that the desired quality attributes of the product will be realized. The acceptability of the end result is ascertained using samples of the completed materials.

Initial and ongoing qualification of production processes are the means for establishing and confirming the experimental experience at significantly larger scales of operation. Knowledge gleaned from the development simplifies later activities. Production processes are always operated within the defined operating ranges because there is no reason to experiment with conditions at the extreme ends of the ranges on this larger scale. Challenges during these stages are primarily in the number of tests performed on the produced materials. Qualification lots are customarily sampled at a substantially higher rate than are routine production lots, and testing of these expanded samples is the challenge of the commercial process. The guidance recommends using appropriate statistical tools in the full-scale qualification efforts to provide the desired confidence in process and product acceptability and thus attain the desired validated state. The expectations for statistical evidence in process validation are well founded; sampling batches at the modest levels associated with pharmacopeial tests provide little, if any, proof of end-product quality. Although those tests may be legally binding, they have only limited value. Industry has largely ignored the levels of "real quality" needed to support its claims for patient welfare (4).

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Keep It Clean | Pharmaceutical Technology

Cleaning and Cleaning Validation—Volume 1, Paul Pluta, Ed., PDA, Bethesda, MD, 2009, 470 pp., ISBN: 978-1933722375

Cleaning and Cleaning Validation–Volume 1 is presented as an all-inclusive reference manual for cleaning-validation. The editor's goal is ambitious, and the result is impressive. This book covers the gamut of cleaning-validation topics in substantial detail, thus helping to equip the reader with a single source of general scientific understanding. It is the first and most general in a series of volumes detailing "current knowledge and approaches to cleaning and validation of cleaning processes," as editor Paul Pluta states in the introduction. Subsequent volumes will offer increasingly detailed, specific information, and the series will aim "to address three fundamental questions of cleaning and cleaning validation: why, what and how," according to Pluta.

The book is logically arranged into four major sections that cover cleaning-validation basics, cleaning chemistry and engineering, residues, and specific residues for cleaning. This organization allows readers to find specific information and related topics.

The book's first section lays a strong framework for its subsequent sections. It first provides insight into process validation in general, and then into cleaning validation in particular. The text details regulatory standards and companies' cleaning-validation policies, and offers guidance for the development of a cleaning-validation master plan. The section's detailed information should prove informative, regardless of the reader's experience level in cleaning validation.

A particularly strong inclusion is a chapter on a quality-by-design template for the development of an efficient and effective cleaning program. A cleaning program can be designed to achieve performance requirements consistently by identifying worst-case operating conditions through small-scale characterization studies, and transferring the knowledge obtained to the full-scale cleaning process. The quality-by-design approach uses a strong scientific rationale to build quality into a cleaning-validation program. The approach, therefore, could significantly enhance the program's robustness and capability.

In the second section, readers will find a brief treatise on cleaning-agent chemistry and mechanisms. In addition to providing a basic understanding of various cleaning agents, this section could help readers choose the most appropriate cleaning agent for their equipment and its materials of construction, thereby optimizing their cleaning effectiveness and consistency. This section is relatively short, but it discusses all key considerations for cleaning-agent selection properly.

The book passes from the general to the specific in its third section, which offers much more detail. Various passages explore residues and residue-grouping strategies, and also present an in-depth discussion of visual cleanliness and its employment in cleaning programs. The discussion of microbial and endotoxin residue helps readers understand regulatory requirements and technical issues associated with the microbial aspects of cleaning validation.

The final section features interesting insights into removing specific residues. For example, the section discusses biotech residues in depth, providing basic biologics and a case study. The section also examines manual cleaning processes and procedures, which are common in the pharmaceutical industry. It is important to understand and control the variability associated with manual cleaning to ensure the quality of a cleaning-validation program.

One of this book's outstanding strengths is its list of contributors, which includes a range of experts in various cleaning-validation disciplines. Individual parts of the book were written by respected academics, product manufacturers, detergent manufacturers, consultants, and regulatory investigators, and their contributions provide a balanced and comprehensive perspective. Each author has many years of experience in his or her field, and most are previously published subject-matter experts.

Cleaning and Cleaning Validation–Volume 1 is a comprehensive general text that would make a great stand-alone reference manual for cleaning validation. Most chapters include many references to current literature, regulatory guidelines, and requirements for cleaning-process validation. Practical information and case-study examples throughout the chapters reinforce the book's technical discussions. This book is a valuable resource for employees involved in developing pharmaceutical cleaning-validation programs.

Richard Hwang, PhD, is senior director of pharmaceutical sciences at Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, tel. 860.715.0296, fax 860.686.8198, [email protected]
. He is also a member of Pharmaceutical Technology's editorial advisory board.

Jack N. Duranto is principal pharmaceutical scientist at Pfizer Worldwide R&D.

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