Navigating Differences Between FDA and EMEA for Regulatory Compliance During Drug Development

Over the last few years, the European and US regulatory authorities have undertaken substantial new regulatory initiatives regarding the conduct of drug development activities and the regulatory approval of Investigational New Drug (IND), Clinical Trial Application (CTA), and New Drug Application (NDA) submissions.

In the European Union (EU), the May 2004 implementation of the Clinical Trial Directive (CTD),¹ involved Good Clinical Practices (GCPs), as outlined in ICH E6,² Good Manufacturing Practices (GMPs),³ and Annex 13 to GMPs, Manufacture of Investigational Medicinal Products (IMPs).⁴ Most notably, for the past two years, the CTA process has been in force in the EU. The CTD and CTA were intended to harmonize early drug development in the 25 member states in the EU. For the most part, these new procedures have been viewed as increased regulation.

On the US side, consistent with the "Pharmaceutical cGMPs for the 21st Century," initiative,⁵ FDA has issued numerous guidelines, including those related to pharmaceutical development (ICH Q8),⁶ Process Analytical Technology (PAT),⁷ and GMPs for early development (INDs—Approaches for Complying with cGMP for Phase 1).⁸ The agency also began a significant new initiative, the "Risk-Based Pharmaceutical Quality Assessment System."⁹

These guidances and initiatives were intended to address the challenges and difficulties facing the newly reorganized FDA Office of New Drug Quality Assessment (ONDQA), concurrent with establishing and nurturing a framework of improvement and innovation in chemistry, manufacturing, and controls (CMC) development. These challenges included the FDA resources needed for generating comprehensive CMC summaries from the raw data in NDAs, multiple CMC review cycles for NDAs, and numerous postapproval manufacturing supplements. These new initiatives focus on critical quality attributes (chemistry, pharmaceutical processes, and product performance) and their relationship to safety and efficacy.

Quick Recap

The new system also relies more on the applicant to provide easily reviewable data in the form of the Pharmaceutical Development and Quality Overall Summary (QOS) section of NDAs. ICH Q8 is intended to provide the regulators with a historical synopsis of the development of a drug product so that the agency may better understand the evolution of the drug and dosage form. Generating more information during development will allow a larger "design space" that is intended to provide additional regulatory flexibility post approval. The new system emphasizes the utilization of the principles embodied in Quality by Design concepts to determine the critical aspects of pharmaceutical manufacturing quality. Although the original intent of these initiatives was to ultimately provide increased regulatory flexibility to implement future (i.e., post approval) changes, they also have clear advantages to streamlining and expediting early CMC drug development programs.

In addition, in January 2006 the FDA issued both a draft Guideline and a final rule related to the cGMP requirements for Phase 1 clinical trials. This guidance said that "...particular requirements in 21 CFR 211 need not be met for most investigational use manufactured for use during Phase 1 development."⁸ The intent of the draft guidance was to codify the principle of a sliding scale of expected compliance during early CMC development and to facilitate the manufacture of investigational drug products for Phase 1 clinical trials. Due to substantial negative comments on the risks to subject safety, however, the final rule was withdrawn in May 2006, but the draft Guidance remains, presumably to be revised based on public comments.

Differences between EMEA and FDA Regulations

Given all these recent developments in the US and the EU, there are several disconnects in expectations between the FDA and the EMEA. These include differences in the coordination between GMPs and GCPs, guidelines governing investigational products, the role of Quality Assurance function, and the way amendments to CTAs and INDs are handled.

Coordination Between GMPs and GCPs

In Europe, GMPs and GCPs are much more closely associated and inter-related than in the US, where they are usually considered as two separate and independent regulations. One has only to examine section 5.14 of the ICH E6 Good Clinical Practice Guideline² to see that the authors of this clinical guideline had an excellent appreciation for the ramifications of inadequate manufacturing or packaging on the clinical program. Scientists involved in the clinical supply chain can attest to the impact of clearly written directions for use on both subject compliance and clinical outcomes. Consider the likely actual dosing by subjects and clinical outcomes if directions were:

• "Take two capsules daily."

• "Take one capsule twice daily."

• "Take one capsule in the morning and one capsule in the evening."

• "Take one capsule every 12 hours with food."

Guidance documents for GMPs for Investigational Drug Products

In the EU, the general GMPs are found in 2003/94/EC, Laying down the Principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational products for human use.³ Greater detail (similar to the level of detail in 21 CFR 211) can be found in the Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practices for Medicinal products for human and veterinary use.¹⁰

A series of Annexes provide details on specific areas of activity; Annex 1, for example, covers the manufacture of sterile medicinal products. Annex 13, "Manufacture of investigational medicinal products [IMP]"⁴ provides 55 suggested approaches in 10 areas (e.g., personnel, premises, quality control, and documentation) that reflect the uniqueness of the clinical supply chain process. Annex 13 also addresses issues such as blinding, the use of comparator products, the use and security of randomization codes, label text, and extra QA controls needed due to the look-alike nature of blinded supplies, which have no equivalent or utility in commercial manufacturing and packaging operations.

In the US, the 1991 FDA Guidance Preparation of Investigational New Drug Products¹¹ identified a dozen areas where the implementation of traditional compliance approaches were difficult or impossible (e.g., process validation). For the most part, alternative approaches were not suggested or discussed. The principle of the January 2006 Draft Guidance INDs—Approaches for Complying with cGMP During Phase 1⁸ was that the requirements of 21 CFR 211 need not be met for most investigational drugs. This statement precipitated substantial negative comments from the industry and the accompanying final rule was withdrawn (although the Guidance remains as a draft). The majority of the negative comments dealt with the risk to the public when these minimum GMPs would not be expected or followed. This guidance provided little in the way of specific alternative practices. In addition, there was no differentiation which and how items listed in the guidance differed from the GMPs described in 21 CFR 211.

The Quality Assurance Function and the Qualified Person (QP)

In the EU, an individual Qualified Person must certify the GMP compliance for each batch of drug product, both commercial or investigational. The responsibilities of the Qualified Person are provided in Annex 16¹² to the EU GMPs. For IMPs, the Qualified Person must also certify that the executed batch records are in concert with the Product Specification File, explained in Annex 13, chapter 9 (see the sidebar) and with the Quality (CMC) section of the IMP Dossier. If IMPs are manufactured or packaged in the US and then imported into the EU, the EU qualified person certification is usually given only after a compliance audit, which is conducted according to EU GMP and Annex 13 standards.

Product Specification File

In the US, the Quality Assurance function is responsible for conducting a production record review according to 211.192 and for ensuring CMC contractors meet GMPs (211.22 a). These basic requirements are the same for commercial and investigational drug products.

In the EU, there is a formal 2-step release process for IMPs (see Annex 13, article 44, and the CTD, 2001/20/EC, article 9). The GMP release involves the certification of the qualified person as described above. The GCP release involves assurances that the CTA has been submitted and a favorable opinion received from the Competent Authorities and the Ethics Committee (in the US, this committee is called an Institutional Review Board, or IRB). In the US, the release process is not codified. It is common for the GCP "regulatory" release to include receipt and review of documents including FDA Forms 1571 and 1572, the investigator's curriculum vitae, indemnification forms, IND submission and 30 day wait and IRB approval. The GMP release is usually based on a batch record review and evaluation of Certificate of Analyses.

Amendments to the EU CTA and the US IND

The European CTA is, on the surface, extremely similar to the US IND. Both involve submission of basic CMC, toxicology, and clinical program information to the appropriate regulatory bodies for review. The depth and extent of the details required are readily available.

In the US, the FDA Guideline on CMC requirements for Phase 1, Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products¹³ briefly describes the CMC information required. In the EU, the websites for the UK's Medicines and Healthcare products Regulatory Agency (MHRA) and the French regulatory authorities contain similar descriptions and excellent examples of the depth of information required; with few exceptions, these requirements are similar to those in the US.^{14, 15} The review timeframe is similar (30 days in the US, 60 days in the EU) although, in practice, many of the competent authorities have consistently completed their reviews in under 35 days.

During early drug development, frequent changes are made to every aspect of CMC development: formulation, ingredients, quantitative amounts, various strengths of the investigational drug products, method of manufacture, scale and batch size, analytical methods, specifications, packaging and labeling. Updates to the IND and CTA are handled by amendments, but there is a substantial difference between the two regions in the way these updates are handled.

In the US, changes to original IND submissions that have safety implications (e.g., a new synthesis route or if large-scale API synthesis produces new or higher levels of impurities than those previously used in toxicology studies) are best handled by amendments followed by verbal or written confirmation that the changes are acceptable. Other updates to the IND may be made without prior approval in an annual report or an information amendment such as the Post Approval Changes Being Effected (CBE) process.

In the EU, updates are made through amendments, which can be classified as major or minor. In the post-2004 CTA era, all major amendments require prior approval from the competent authorities, yet even in 2006, there is a lack of agreement among the 25 member states about what constitutes a major amendment. For example, in the UK, the MHRA expects to formally review and approve the original and any extensions to the provisional or tentative expiry (or shelf life or retest) date, and has requested the actual stability data that were used by the sponsor to project the expiry date.

US Initiatives to Link Regulation to Good Science

In the US, several initiatives have been undertaken to link regulatory expectations to good science. These include the promulgation of several guidance documents, such as ICH Q8, Product Development, ICH Q9 Quality Risk Management, and the process analytical technology (PAT) guidance. FDA also undertook an initiative on manufacturing science, formed the pharmaceutical inspectorate, and is involved in the development of the ICH Q10 guidance on continuous improvement.

Product Development Report (ICH Q8)

The ICH Q8 guideline describes the the Product Development Report (section 3.2.P.2 of the CTD), which can be a valuable tool for firms that perform adequate and focused product formulation research. The use of this report encourages and allows firms to share with regulatory reviewers the evolution and refinement of their products. When properly executed, it can elucidate the design, understanding, and control of the production process and the choice and control of excipients, as well as provide a basis for identifying Critical Quality Attributes. The report provides an expanded knowledge document that defines the product and process such that regulatory flexibility becomes "built-in"—from both an understanding and decision perspective. For most dosage forms, the document does not have to be expansive, but rather a concise historical synopsis.

Quality Risk Management (ICH Q9)

The ICH Q9 document, Quality Risk Management¹⁶ has recently been adopted and implemented by FDA, and agreement on terminology and compilation of risk assessment tools has been accomplished. The document was not intended to be a step-by-step manual, but rather defines and suggests strategies for examining risks in production and discusses implementation. It represents a collection of tools that can be used to analyze production risks (e.g., Failure Mode Effects Analysis, FMEA) for incorporation into existing quality systems. The concepts of risk management can be adopted during research and development, and when they are applied to R&D as part of an expanded knowledge base, problems and setbacks that are endemic to CMC development can be minimized.

Continuous Improvement (ICH Q10)

Although it is not yet finalized or adopted, ICH Q10 represents some of the most current thinking with respect to pharmaceuticals manufacturing and control. It is an attempt to capture the concept that cGMPs or the ISO 9000s alone cannot provide effective systems for allowing process improvements over the life of the product in a less burdensome manner. It shifts responsibility for managing "low-risk" changes to the manufacturer's quality system. The FDA has responded by publishing a companion guidance on quality systems¹⁷ that details a more holistic approach to quality management for pharmaceutical manufacturing. In the future, pharmaceutical producers would be well advised to use product development as a tool to map out and support possible product changes and variations based on product and process knowledge. Forethought can neatly tie together product development, process development, process analytical technologies, and risk-based decision making.

Process Analytical Technology (PAT)

The 2004 publication of the FDA's guidance on process analytical technology, PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance⁷ represented the first time the FDA formally emphasized process understanding as central to controlling product quality. PAT emphasizes the incorporation of in-line, at-line or on-line analytical methods (e.g., NIR, Raman, micro-chromatography, etc.) that allow for real-time monitoring of production. Coupled with appropriate data collection and analysis systems, product quality can be monitored and controlled during the manufacturing process, thus reducing the amount of release testing required at the end of the manufacturing process. It allows for continuous quality monitoring as well as better process control. The caveat is that one must understand the formulation and how it is manufactured. The FDA has assembled, trained and certified a PAT Team that includes CMC and microbiology reviewers (for new and generic drugs), compliance staff, and field investigators for the purpose of evaluating these types of product applications.

Manufacturing Science and the Pharmaceutical Inspectorate

Within FDA's Center for Drug Evaluation and Research (CDER) and the Office of Pharmaceutical Science's (OPS) Office of New Drug Quality Assessment (ONDQA), a small, specialized review group has been assembled and established. This Manufacturing Science Team is a group of reviewers drawn from various backgrounds who have hands-on manufacturing experience in the pharmaceutical industry. All have had development, scale-up, or production experience in areas such as bulk raw materials and dosage form production. The team's focus will be on the distinctly manufacturing sections of NDA submissions—a more specialized review team approach. These efforts will be coupled with increased emphasis on integrating the review and inspection processes—i.e., facility inspections that involve both a field investigator (such as a member of the new Pharmaceutical Inspectorate cadre) and a CDER CMC reviewer. In this manner, both the scientific soundness as well as the compliance aspects can be discussed and agreed upon in a more complete fashion at the time of inspection and evaluation. Through efforts like these, the agency hopes to achieve more balance between scientific review and compliance/field activities, with the aim of ensuring that drug products are produced in a reliable and reproducible manner and that manufacturing methods can be improved over time with more regulatory flexibility.

In the Fall of 2005, FDA announced a pilot program¹⁸ that sought volunteer firms to participate in submitting NDAs or postapproval change submissions that incorporate the principles discussed here. In doing so, the agency is attempting to encourage companies to implement quality-by-design concepts, product development submissions, product design space, risk-based product controls, process analytical technologies, and continuous improvement planning in new applications. This pilot program is ongoing and will be evaluated for effectiveness at the end of the pilot program period.

The FDA also has responded to the challenges outlined above by moving to streamline CMC review and promote drug quality. It has proposed a more comprehensive team approach to product evaluation. Within OPS and ONDQA, staff are focused on bringing together the appropriate skills and specialties to review a specific product. At the same time, the agency is encouraging communication and discussion between headquarters reviewers and field investigators (e.g., Pharmaceutical Inspectorate or PAT Team members) so that a product can be evaluated for scientific content as well as compliance in a more thoughtful and coordinated manner. The long-term goals include regulatory flexibility and appropriate scientific product quality controls.

In the future, pharmaceutical firms, nonprofit institutions, and academic research centers would be well advised to take advantage of the new globally developing paradigm. A carefully executed product development project will incorporate some or all of the concepts mentioned above to achieve a deeper understanding of the drug and allow for postapproval improvements with more regulatory flexibility. But the primary reason for adopting research and development approaches that are consistent with these initiatives appears to be a higher comfort level that CMC development will proceed more smoothly, without delays caused by inadequate knowledge or ad hoc experimentation.

JOHN E. SIMMONS, PhD, formerly a senior scientist at FDA's Center for Drug Evaluation and Research, OPS/Office of New Drug Chemistry, is currently president of Simmons FDA CMC Consulting, LLC, 323 Night Harbor Dr., Chapin, SC 29036, tel. 240.888.5726, Simmonsfdacmc@aol.comDAVID BERNSTEIN, PhD, is president and CEO of Bernstein CMC Regulatory Consulting, tel. 510.658.3334, david@bernsteincmc.com

References

1. European Commission Directive 2001/20/EC. Clinical trial directive. 2004 May. Brussels, Belgium. Available from: www.ec.europa.eu/enterprise/pharmaceuticals/pharmacos/dir200120ec.htm.

2. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. E6: Good Clinical Practice. Geneva, Switzerland. Available from: www.ich.org.

3. European Commission. Directive 2003/94/EC, Laying down the Principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational products for human use. Brussels, Belgium. Available from: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev1.htm

4. European Commission. EUDRALEX, Vol. 4, Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice. Annex 13, Revision 1. Brussels. 2003 July. Manufacture of investigational medicinal products, Available from:

5. US Food and Drug Administation, Rockville, MD. Pharmaceutical cGMPs for the 21st century—A risk-based approach. Press Release, Aug. 21, 2002, Available from: www.fda.gov/oc/guidance/gmp.html and Final report, Fall 2004. Available from: www.fda.gov/Cder/gmp/gmp2004/GMP_finalreport2004.htm and

6. FDA. Guidance for industry. Q8. Pharmaceutical development, Available from: www.fda.gov/cder/guidance/6746fnl.pdf.

7. FDA. Guidance for industry. PAT—A framework for innovative pharmaceutical development, manufacturing, and quality assurance. Available from: www.fda.gov/cder/guidance/6419fnl.htm.

8. FDA. Guidance for industry. INDs—Approaches to complying with CGMP during Phase 1. Available from: www.fda.gov/cder/guidance/6164dft.htm.

9. FDA. ONDC's new risk-based pharmaceutical quality assessment system. 2004 September 29. Available from: www.fda.gov/cder/gmp/gmp2004/ondc_reorg.htm.

10. European Commission. Enterprise and Industry. Rules governing medicinal products in the European Union, Volume 4, Good manufacturing practices for medicinal products for human and veterinary use. Available from: pharmacos.eudra.org/F2/eudralex/vol-4/home.htm.

11. FDA. CDER. Guideline on the preparation of investigational new drug products (human and animal). 1991 March. Available from: www.fda.gov/cder/guidance/old042fn.pdf.

12. European Commission. Volume 4. Good manufacturing practices. Annex 16. Certification by a qualified person and batch release. 2001 July. Available from: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev4.htm

13. FDA. CDER. Content and format of investigational new drug applications (INDs) for Phase 1 studies of drugs, including well-characterized, therapeutic, biotechnology-derived products, 1995 November. Available from: www.fda.gov/cder/guidance/clin2.pdf.

14. Medicines and Healthcare products Regulatory Agency. www.mhra.gov.uk.

15. French Health Products Safety Agency, www.afssaps.sante.fr

16. FDA. Guidance for industry Q9 quality risk management Available from: www.fda.gov/cder/guidance/7153fnl.htm

17. FDA. Guidance for industry. Quality systems approach to pharmaceutical current good manufacturing practice regulations. 2004 September. Available from: www.fda.gov/cder/Guidance/6452dft.htm

18. Federal Register September 19, 2005. Submission of chemistry, manufacturing, and controls information in a new drug application under the new pharmaceutical quality assessment system; Extension of application and comment deadlines. Available from: www.fda.gov/OHRMS/Dockets/98fr/05-18515.pdf.