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),

  involved Good Clinical Practices (GCPs), as outlined in ICH E6,

Manufacture of Investigational Medicinal Products (IMPs).

 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,

  FDA has issued numerous guidelines, including those related to pharmaceutical development (ICH Q8),

INDs—Approaches for Complying with cGMP for Phase 1

  The agency also began a significant new initiative, the "Risk-Based Pharmaceutical Quality Assessment System."

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.  

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 

 211 need not be met for most investigational use manufactured for use during Phase 1 development."

  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.  

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 Guideline

  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 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.

 Greater detail (similar to the level of detail in 21 

Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practices for Medicinal products for human and veterinary use

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]"

  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.  

Preparation of Investigational New Drug Products

 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 1

 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 

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 16

  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. 

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 c

, 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. 

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 Products

 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.

  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 

 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, 

, 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.  

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. 

The ICH Q9 document, Quality Risk Management

  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. 

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 systems

  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.  

The 2004 publication of the FDA's guidance on process analytical technology, 

PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

 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 program

  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. 

Articles

While not yet finalized and adopted, ICH Q10 represents some of the most current thinking with respect to pharmaceuticals manufacturing and control.

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

One of the challenges faced by the pharmaceutical industry in today's global economy is the successful release of commercial drug products in multiple markets. 

When the commercial release of a drug has to be accomplished simultaneously from different sites, the establishment of the proper infrastructure ensures equivalent analytical results across the various laboratories.  

Thoughtful coordination and implementation of the highest quality standards involves expert training, compliance with established standard operating procedures, analytical methodology, validated instrumentation, availability of critical reagents and reference standards, and a uniform materials and documentation practice across analytical laboratories. The result is a successful technical transfer of products. 

Particularly challenging is product release of commercial biopharmaceuticals. Careful planning and preliminary considerations ensure a successful technical transfer.

  In the case of biopharmaceuticals, analytical methods are often quite complex. For commercial product, the methods are fully validated and the biopharmaceutical product has been well characterized by the originating laboratory.

As a case study, the experience of Wyeth Research in the successful technical transfer of bioanalytical product release methodology to the Japanese and European markets is discussed.  

 The goal is to provide adequate training to the receiving laboratory analysts and ensure compliance with procedures established by the originating laboratory while minimizing variability in analytical results. This will likely entail direct training by the transferring laboratory. Established, fully validated methodology and SOPs are required before  initiation of any training activities. Coordination of training requirements among sites must include verification of equivalent training practices while considering each site's unique needs. Additionally, qualifications of the analysts to be trained must be documented. 

In our own experience, a visual training presentation was instrumental in overcoming unexpected language barriers. 

All documentation encompassing validation of analytical methods, SOPs, reagents, certificates of analysis/origins of materials, instrumentation equivalence, equipment qualification status, personnel training, and facilities certificates must be reviewed and compiled in compliance with regulatory agencies from both ends of the transfer. In the case of biologicals, additional safety parameters, such as biohazard exposure and adequate training of personnel in biomaterials handling, are essential. Regulations pertaining to the licensing permits and qualifications of the receiving laboratory in handling items such as radioactive materials or biohazard or pathogenic materials also must be examined and may vary on a case-by-case basis. Procedures must be verified to meet compliance requirements with national regulatory agencies governing the receiving laboratory. 

 The primary responsibility of the releasing analytical laboratory is to produce the highest quality data and corroborate product integrity, thereby ensuring the safety of patients receiving a drug product. It is essential that the releasing laboratory acquire not only pertinent analytical methodology, but also develop scientific expertise and become fully acquainted with all aspects of the drug characteristics prior to release to the public. Open communication channels must be established to ensure that adequate knowledge about the drug product is transferred from the originating laboratory to the receiving laboratory during and following completion of the technology transfer training activities. 

The limits of parameter variability discovered during method validation for a given analytical test are de facto verified during the technical transfer. The design of a high-quality analytical variability matrix during method development and subsequent validation is essential to provide satisfactory outcomes in parameters such as robustness and reproducibility at the time of method transfer. This kind of expertise is challenging to transfer to the downstream laboratories in a limited time frame. Side-by-side training is highly recommended to acquire all pertinent method details and the proper criteria to identify and correctly attribute the source of parameter variation results, to ensure minimal interlaboratory result variations, or to accommodate the use of equivalent, but nonidentical, analytical instrumentation. Additional considerations taken for the establishment of equivalence of compendial methods between countries include, for example, content uniformity and moisture. The 

) has three compendial methods for water determination <921> 1a, 1b and 1c, whereas the European Union uses mostly method EP (2.5.12), which is equivalent to  

; determination of content uniformity in 

, even if it is considered an equivalent method to 

<905>, has differences in the way the results are calculated and reported. 

Acquisition of truly equivalent instruments might mitigate potential variability in results later on. In one case, negotiations to acquire equivalent instrumentation were not productive and equivalency between two instruments had to be established relative to a third standard instrument. Eventually, the receiving laboratory agreed to consider purchasing an equivalent instrument. 

 The decision to set up acceptance criteria should be based on the receiving laboratory's ability to perform the method successfully. The criteria for interlaboratory variability during method transfer should not be confused with method variability and must be weighed against the precision of the instrumentation used for the particular method and biopharmaceutical drug specifications. Interlaboratory variability acceptance criteria are method dependent and require careful examination of each individual method documented in the transfer protocol. The handling of potential deviations from the acceptance criteria should be clearly defined in the transfer protocol and a remediation plan should be instituted prior to initiation of transfer testing. All deviations must be reported and documented as an addendum to the original transfer protocol. 

In our experience, the preset acceptance criteria for one analytical method resulted in an out-of-specification (OOS) investigation by the receiving laboratory. This situation could have been avoided if adequate acceptance criteria accounted for a realistic analyst-to-analyst variability. 

 Specifications for a given biopharmaceutical might be considered too broad for the receiving regulatory agencies at the time of product release. Specifications are intrinsically associated with the nature of the biopharmaceutical product and the precision and sensitivity of the analytical method and instrumentation used; specifications also should be independent of analyst variability. Suitable specifications are typically refined during the development of the drug product candidate and finalized before its commercial launch; their acceptable ranges must be narrowed to meet or surpass acceptable ranges in accordance with the International Conference on Harmonization (ICH) guidelines, in addition to those specified by the intended market regulatory agencies.  

 Reference standards and critical reagents should be provided to the receiving laboratory to cover transfer protocol testing and should include additional material for practice testing. For biopharmaceuticals, analytical reagents may not be commercially available. A reasonable inventory supply tracking system must be established by the transferring laboratory to maintain a log of critical reagents supply required to cover the needs of all release laboratories for long-term release testing. Additionally, a regular supply chain must be established to the receiving laboratories. Not to be forgotten are valid import permits to allow customs release of the shipped materials. Chain of custody procedures and environmental monitoring are customary for all shipped critical reagents used for testing under a Current Good Practices cGXP setting (i.e., cGMP, cGLP, cGCP). 

In our experience, unexpected situations have occurred and one must be prepared to handle them decisively. As an example of critical reagent transfer surprises, the establishment of a good working relationship with the contracted international courier was instrumental in preventing the loss of a dry ice shipment during a particularly hot summer week at a European port of entry. To compensate for an unexpected delay in shipment relays caused by an airport controller strike, the courier contacted its local office, rented a truck, and drove the shipment overnight through two countries to deliver the critical reagents safely. 

 Direct communication among all parties involved in the technical transfer before and during preparation of the draft protocol document should be encouraged. Prior expertise in the technology transfer process facilitates the inclusion of well-defined responsibilities, organization of the transfer program, and lessening of avoidable protocol amendments. Communication may include both the transfer and receiving laboratories, the technical transfer officer, and the quality units from both sites. Whenever possible, teleconferences should be scheduled (taking into account time differences) to allow for direct discussions to clarify any issues. The transferring laboratory's expertise should be openly disclosed to discuss any questions or expectations by the receiving laboratory during protocol preparation. Sensitivity to different cultural backgrounds and potential language barriers may need to be addressed. 

As an example, due to language subtleties, the receiving laboratory may erroneously interpret a procedure described in a method. This situation can be avoided with side-by-side training and clarification of any statements perceived as vague. 

Once the technical transfer protocol has been prepared and approved, it is desirable to provide direct training to the receiving laboratory before protocol execution. The complexity of the training for release testing may vary according to the complexity of the analytical methods involved. There are no perfect methods, and often, direct visual demonstration of procedures such as sample preparation, handling, and sample application can avoid erroneous method interpretations arising from language nuances. In addition, training on specialized software for data analysis may be included as needed. Analytical data analysis templates should be prepared ahead of time for the receiving laboratory, as well as accompanying examples of representative data. Simultaneous training of two analysts is preferred, although we have successfully transferred multiple methods to a single analyst. The transferring laboratory must carefully coordinate side-by-side training activities to allow sufficient time for completion of all methods by trainees. Contingency plans for repetition of side-by-side training in case of technical failures are not required, but highly recommended. Our policy requires that all original training records of the receiving laboratory analysts must be documented and retained according to the practices of the transferring laboratory regardless of the documentation practices for training at the receiving laboratory. 

 Once preliminary training is completed, execution of the preapproved technical transfer protocol may take place at the transferring and receiving laboratory sites. Each method will dictate the need for equivalencies in instrumentation between laboratories. Parameters to consider in addition to system suitability include instrument performance tests, lot-to-lot, and interlaboratory variation at the time of data review. In the case of commercial product, the analytical release method needs to be fully validated per ICH guidelines

; thus, transfer of commercial release methods must comply with guidelines and be reflected in the transfer protocol document. Samples used for method transfer testing need not be from commercial lots, and may be representative samples. The advantage of using freshly manufactured and released batches as the choice for technical transfer protocol execution obviates the need of retesting at the time of transfer by the transferring laboratory. The transfer training measures the ability of the receiving laboratory to perform the testing from the transfer laboratory within the preset acceptable criteria limits.  

Analytical data should include tabulated values from each laboratory, standard deviations, and coefficients of variance to establish meaningful statistical correlations in interlaboratory or instrument-to-instrument variations, for instance. Free exchange of analytical results should be encouraged to facilitate satisfactory completion of the protocol. If commercial lots are used for analysis, the transferring laboratory may provide the original results from the product release certificate of analysis. The choice of sample lots should be considered carefully to include samples whose analytical values are representative of the entire range of specifications. For example, results in the average range should be used along with lots trending towards high and low ends of the specifications. This practice might be more challenging, given the expected higher analyst variability during initial tests at the time of training, but it will ensure better consistency at the time of true product release. On completion of data analysis, conclusions of the successful completion of transfer should be documented and included in the protocol for final review and approval. 

Procedures detailing the handling of laboratory test result failures should be compared between both transfer sites and a common remediation practice procedure should be established and included in the transfer protocol. In the case of simultaneous commercial product release from multiple sites, procedures for handling result discrepancies should be established prior to the initiation of release testing. In the case of biopharmaceutical sample preparation, handling, storage, and stability are critical parameters for correct analytical testing. 

The complexity of the technology transfer analytical methodology dictates most of the aspects of design and acceptance criteria for the transfer protocol. As a reminder, the length of timing between technology transfer training and authentic product release testing must be taken into account and communication continued to provide training refresher support as needed. 

The authors are members of the Analytical and Quality Sciences Laboratory, Preclinical Development department, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, 845.602.4981, 

 1. Bioanalytical Method Validation, guidance for industry, USD-HHS, FDA-CDER, FDA-CVM, May 2001. 

 2. Text on Validation of Analytical Procedures, ICH guidelines Q2A, 27 Oct 1994. 

 3. Validation of Analytical Procedures: Methodology, ICH guidelines Q2B, 6 November 1996. 

 4. Specifications: Test Procedures and acceptance criteria for Biotechnological/Biological Products, ICH guidelines Q6B, 10 March 1999. 

 5. Scypinski S, Roberts D, Oates M, Etse J. Analytical Method Transfer, draft guideline, Pharmaceutical Research and Manufacturers Association (PhRMA) Acceptable Analytical Practices, Pharmaceutical Technology Europe, March 2002. 

 6. Krause SO. A guide for testing biopharmaceuticals-Part 1: general strategies for validation extensions. Pharmaceutical Technology Europe, May 2006. 

 7. Lutz H. Introduction to Validation of Biopharmaceuticals, BioPharm International, March 2005. 

 8. European Pharmacopoeia, 5th Ed. 5.5, Assay Method 2.5.12 

 9. The Japanese Pharmacopoeia, 14th Ed. Part 1, General Test 10. 

Established, fully validated methodology and SOPs are required prior to initiation of any training activities.

Expediting the Technical Transfer of Biopharmaceutical Products

Development reports document process development and support the design of validation experiments, yet in many firms training is not provided nor are expectations established. This article describes how project managers can help scientists master the art of report-writing.  

Many scientists are expected to write and review development reports, but do not understand their purpose, and give these tasks low priority. Reports are necessary to: 					

accurately record what was known during development, and when

document the science behind a patent application and provide technical review; to aid in preparation of the patent application

prevent reinvention or repeat experimentation by documenting results in a central file 

summarize experiments and provide interpretations in support of patents, regulatory filings, and product claims

meet regulatory requirements of recording a process history and history of change, with rationale

ensure that material submitted for external publication is widely available internally, and captured in a filing system

Writing reports can also provide added perspective, stimulate new interpretations, and help an employee achieve a promotion or other career goal.  

Many activities compete for time and attention in the typical biopharmaceutical firm. You can encourage interest in writing by making sure scientists: 					

understand company expectations for quality, quantity, style, and time frames 

understand deadlines, and know there will be consequences for not meeting them

do not procrastinate, which can lead to decreased standards as deadlines approach

The single most important action you can take to facilitate writing is to assemble the team of authors (and reviewers) and talk about challenges, problems, and potential solutions. Ask the following questions: 					

What barriers and obstacles are in the way for authors? For reviewers?

How can reviewers make it easier for authors?

How can authors make it easier for reviewers?

				Often, a simple list of ground rules can be generated and agreed upon, such as establishing deadlines and managing expectations 			

Writers and reviewers should be trained and provided the tools of the trade. Training can be done individually or in groups.  

Table 1.  Typical gripes about reports 			

Your English teacher was correct: outlines help when writing a report. Table 2 shows an example of a template that can help an author begin to draft a new report. Many writers have said that the template has helped them to begin and to identify gaps or questions. The template also provides, at the start, a documented agreement with reviewers. One author commented that it was a big step forward simply to know who would be doing the review before the writing began.  

Table 2.  Outline template for development report			

Tool #2:  Templates and examples of reports

Do your scientists prefer templates, which they use in every report, or new structures for each different document? Often, scientists want both. A template is fine if it works for the author and is not overly restrictive.  

Anyone who has pasted together a document from parts contributed by several authors understands the frustration and time involved in reformatting. Templates can help to minimize unnecessary confusion. The template not only looks more professional, it assists in the review process. All stakeholders become accustomed to the template and know where to look for particular information. It may be a good idea to start with a very simple template, and offer more complex templates later on. The authors should have input into template design.  

If your firm does not have templates, you could use an existing report as an example and ask authors to follow its style, length, and formatting. As more reports are created, the example can be updated. 

Table 3 lists templates that are often used for development reports.  

Table 3.  Types of templates for reports			

Boilerplate text is generic information that can be pasted into any document and used repeatedly. These texts, which do not need to be re-edited each time they are used, promote consistency and uniformity and provide the author with ready-to-use material. Boilerplate text can be preloaded into templates and used or deleted, as appropriate.  

Tool #4: Differentiate the Types of Reviews

Although biopharmaceutical companies sometimes offer writing instruction, they rarely offer instruction for reviewers. Omitting training for reviewers places a heavier burden on the author, who must reconcile conflicting feedback and finish the report on time. Training can be conducted in individual or group settings, for a specific report, or a group of papers. Different types of articles require different types of reviews. For example: 					

 Reviewers, usually managers or supervisors, check for thoroughness of content and make sure there is enough information to support the conclusions. This type of review is usually left until last, to give the author as much time as possible to write and edit.

 At some point, all data, calculations, and manipulations should be reviewed by a second person to check for errors. At the same time, the traceability of the data—the ability to trace back from the report to the original raw data in laboratory notebooks, records, or computerized data records—can be checked. A requirement of cGMP, this step is important even for early research data, if important decisions and claims will be based on the data. Once data have been reviewed, they should be placed in a format protected from accidental loss or change, such as a .pdf instead of a spread sheet.

 The entire report must be reviewed to ensure that conclusions are supported by the data, appropriate earlier work is cited, and science is sound. The reviewer should also ensure that statistical tools used are appropriate, that all assumptions appear to be scientifically valid, and that experimental controls are complete and adequate. The reviewer should ask, "Did it work? Are the conclusions believable?"

 The reviewer should check grammar, spelling, and punctuation for correctness, and check for clarity and readability. A copy editor asks the author to explain ambiguous passages and may suggest simplifying sentences or changing the order of sentences to facilitate reader comprehension.   

Most reviewers begin to copy edit the article from the start but this may result in well-worded descriptions of experiments that should not be included in the report. Copy editing is the one type of review that can most easily outsourced. Copy editors are much less costly than scientists, and can greatly improve the quality of written output without slowing it down. Scientists who publish in journals will be familiar with this step, which occurs after their manuscript is reviewed and accepted for publication.   

 In the final step before publishing, spelling, numbering and cross-references are checked for errors.  Usually, this step involves the author and a document specialist.

Development reports document process development and support the design of validation experiments, yet in many firms training is not provided nor are expectations established. This article describes how project managers can help scientists master the art of report-writing.

Writing Effective Development Reports

Every year, the US Food and Drug Administration issues scores of Warning Letters to pharmaceutical, medical device, and biologics companies. Although Warning Letters can be triggered by situations such as customer complaints and whistleblower statements, the majority follow an inadequate company response to a Form 483 issued by FDA after an on-site inspection has identified potential violations of regulatory requirements.  

Surprisingly, many companies' violations center on failure to have, or to properly use, Standard Operating Procedures (SOPs), the most fundamental component of current Good Manufacturing Practices (cGMPs). Although different regulations apply to each of the life sciences sectors, SOP compliance is required for all companies within those business arenas.  

The purpose of an SOP is straightforward: to ensure that essential job tasks are performed correctly, consistently, and in conformance with internally approved procedures. Clearly, employees' correct, consistent performance of essential job tasks is as much a business and quality issue as it is a regulatory requirement.  

By its nature, poor employee performance has a negative impact on overall operational performance. That impact may be even greater than recognized by many organizations, with some studies suggesting that up to 40% of operational inefficiencies can be attributed to employees' failure to fulfill their job responsibilities. Even companies that have implemented costly process improvement systems continue to feel the operational impacts of "human error" on their efficiencies and quality control.  

Few industries are more vulnerable to risk than the life sciences sector. Although all industries share a financial vulnerability resulting from operational inefficiency, the liability associated with compromised product quality can hit a life sciences company particularly hard. Compromised product quality can easily result in product recalls, regulatory enforcement, and governmental litigation, but even the suspicion of quality problems can send patient, healthcare professional, and stakeholder confidence plunging. With highly publicized product recalls still fresh in the minds of the public and regulators, life sciences companies and their products are coming under greater scrutiny than ever before. And, because FDA's Warning Letters are public information, public scrutiny is quickly fueled by news reports via the media or the Internet. 

Although FDA has long emphasized the importance of SOP compliance, the Agency's evolving focus on quality as the driver of compliance adds weight to the importance of a comprehensive corporate approach to development and use of SOPs. Warning Letters routinely conclude with a sober reminder that "... violations may result in FDA taking regulatory action without further notice to you." FDA has an arsenal of actions it can impose, from confiscating product inventory to initiating product recalls, assessing civil penalties and fines, or pursuing criminal prosecution. 

FDA's definition of an SOP is deceptively simple. SOPs are, according to a variety of FDA regulations, written procedures that accurately describe and detail essential job tasks. For example, in 21 

 211.100, the regulation states: "There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit." 

Beyond the written procedure, SOP compliance includes a requirement to train employees on essential job tasks, something expressed in 21 

 211.25, which applies directly to the pharmaceutical industry, but is applicable to all life sciences industries. "Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, experience, or any combination thereof to enable that person to perform the assigned function." It is this combination of written procedure and employee training that assures the quality of a drug product or medical device being tested or manufactured and its compliance with applicable FDA regulations. 

Understanding the purpose of SOPs is one thing; complying with the FDA's regulatory standard for ensuring that employees have the knowledge they need to perform their job functions is something else entirely. Large companies may have thousands of job tasks, each one requiring an SOP that usually needs regular updating. Even small companies will have extensive SOP requirements, whether it's for regular equipment calibration or for sterile manufacturing procedures. In fact, FDA has specifically identified operational areas that fall under cGMP and—by extension—SOP regulation. The components for which employees must have sufficient knowledge to perform their job functions adequately, range from buildings and facilities to equipment, components, and drug product containers and closures, production and processes, packaging and labeling, holding and distribution, laboratories, and returned or salvaged drug products. 

In general, SOP compliance incorporates activities that can be grouped into five categories: 

1. Creation of a quality control unit responsible for ensuring SOP compliance 

2. SOPs for each job task that are updated and understandable to employees 

3. Accurate, timely distribution of SOPs to all responsible parties, validation that the SOP has been received and read 

4. Confirmed employee comprehension of the SOPs and the ability to apply the knowledge contained in the SOP 

5. Comprehensive corrective and preventive action program to identify rectify and prevent quality failures. 

FDA signaled a new approach to cGMP compliance by pharmaceutical and biotechnology companies in September 2004. The Agency's "...modern quality systems and risk management approach" to cGMP emphasized management responsibilities for quality control and assurance. That responsibility included formation of a quality control unit that "... shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products." Although the compliance responsibility of the quality control unit is not limited to SOPs, an effective SOP compliance program is central to the unit's ability to fulfill its mandate. 

Although life sciences companies routinely embrace the most advanced technologies in the laboratory and manufacturing plant, many companies have not been as receptive to technology managing their SOP activities. Given the scope of modern SOP compliance responsibilities and the consequences of noncompliance, companies increasingly recognize the value of using technology to comply with SOP mandates. Not coincidentally, the same system that supports SOP compliance can also easily serve as the foundation for improving a company's overall quality control management and assurance effort. 

An effective SOP compliance program requires a technology-enabled platform that is interoperable with existing technologies and performs multiple functions, including SOP distribution, validation, testing, and recordkeeping in audit-ready formats. Because SOPs require revision with every process change, equipment replacement, or regulatory change, any SOP management technology should enable rapid updating and distribution. Just as important, the system should allow effective targeting of SOPs to the correct employees, thereby preventing all employees from being overwhelmed by SOPs not applicable to the individual's job tasks. 

The FDA requires that SOPs be in a written format. Violation of that basic requirement is routinely found in FDA's Form 483 or in Warning Letters for a variety of operations throughout the regulated process. Significant deviations noted by FDA in recent Warning Letters illustrate the range of activities that may be targeted for failure to meet the written SOP standard. For example: 

1. Failure to establish and follow appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile 

2. Failure to establish written procedures applicable to the function of the quality control unit 

3. Failure to establish written procedures for evaluating quality standards of each drug product to determine the need for changes in drug product specifications of manufacturing and control procedures 

4. Failure to develop written procedures for surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences 

Although SOPs vary from company to company—and sometimes from facility to facility within the same company—they should all have a consistent format that reflects applicable regulatory compliance requirements and includes "how-to" information specific to the job task (Figure 1).  

Figure 1. An example of a standard operating procedure			

Because the purpose of an SOP is to ensure consistent, compliant performance of employees and processes, it goes without saying that SOPs should be understandable to users. Unfortunately, many SOPs are not. The FDA requires that authors of SOPs be qualified individuals with necessary technical and compliance experience and expertise in the particular subject matter addressed by the SOP. Yet, those qualified authors, despite their experience and expertise, may lack the necessary writing, instructional design, and technical skills to effectively communicate with workers with different learning needs. In addition to varying literacy levels, companies increasingly face the challenge of presenting SOP information in multiple languages, or in conformance with different cultural norms. That challenge is unlikely to shrink. Even as life sciences companies continue their global expansion, they are likely to be held to the same SOP requirements, either imposed by FDA or by comparable regulatory authorities in other countries. 

Fortunately, technology now offers alternatives to the infamous SOP manual that afflicted generations of employees with incomprehensible material. Internet-based technologies can produce SOPs that cut through the fog created by pages of written explanations. Graphics, animation, sound, and simulation can be employed to illustrate proper procedures and processes, rather than merely explain them. Skillful use of these instructional techniques can engage employees and enhance comprehension, ensuring that the SOP's intent is achieved. Optimally, SOPs are developed by teams of professionals, equally proficient in the subject matter as in technology, the learning psychology of adults, and interpersonal communications.  

SOP distribution may appear simple and easy. It is neither. Hundreds or thousands of SOPs that change regularly with any shift in regulation, corporate policy, or production process can easily affect hundreds or thousands of employees. It is not unusual for employees to experience, within a relatively short period of time, SOP versions one, two, and three for the same job task.  

The FDA requires that SOPs be distributed in a timely manner and that each employee validate the receipt and understanding of it. The volume of material that must be distributed, validated, and stored virtually requires a technology-enabled system, such as an Electronic Data Management System (EDMS). Dozens of vendors offer SOP or document management systems, but not all systems are equal. An optimal system must comply with all Part 11 regulatory requirements, provide secure access for program monitoring and management, and store data in an audit-ready format that is quickly available for FDA examination during an inspection or investigation. 

The days of simply distributing information to fulfill regulatory requirements are long gone. Today, the standard of SOP compliance requires that SOPs be applied. "Failure to follow written procedures" occurs frequently in FDA's 483s and Warning Letters, suggesting that employees neither understood nor applied the necessary knowledge to properly fulfill their job responsibilities. Interestingly, many of these violations occur in companies compliant with basic SOP requirements related to written procedures, and distribution and validation of employee receipt and understanding of the SOP. Yet, those same companies often lack a mechanism to confirm comprehension. 

All SOP programs should incorporate testing or evaluation features that clearly establish an employee's level of comprehension for any individual SOP. Online-based testing gives managers immediate access to this information, promoting timely responses to identified knowledge gaps. Just as important, testing documentation assures regulators of a company's commitment to effective employee education rather than simple document distribution. 

The obvious intent of an FDA Form 483 or Warning Letter is to promote prompt, voluntary corrective action to inadequacies uncovered during FDA inspections. The 483 gives inspected facility owners the first opportunity to correct compliance violations and implement procedures to prevent them from occurring in the future. Warning Letters are issued for significant regulatory violations that warrant enforcement action if they were not corrected. Often, an inadequate corporate response to a 483 is followed by a Warning Letter that concludes, "Please advise the Agency regarding your corrective action plan to address the problems described above..." and sets a firm deadline for a written response. 

A Warning Letter opens the door for a company to work with FDA in achieving compliance. Responding to the Letter effectively is the first step, and it is a critical one, to minimize the likelihood of an FDA enforcement action. Several factors should be considered in developing a response to an SOP-related Warning Letter, including: 

1. Warning Letters can indicate isolated violations or systemic problems throughout an enterprise. Inadequate SOP training observed by FDA in one job function at one facility may indicate a much broader problem. Understanding the potential scope of the problem, rather than simply focusing on a specific violation noted in the Warning Letter, will enable the company to respond to all violations and improve its own compliance performance. If you disagree with the facts or analysis by FDA, or if you believe no additional actions are necessary for an identified violation, explain your position clearly to FDA. Remember, however, that FDA has the final word. In a 2004 Warning Letter, for example, FDA responded to the company's assertion that "The need and adequacy of training is routinely assessed as part of the internal audit program. We have no evidence that there are systemic training issues." FDA writes, "The production mistakes of two reportedly trained employees, the failure of a supervisor to properly document employee training, and the failure of your internal audit process to identify these weaknesses, suggest that there are problems requiring your attention." 

2. Prepare a response to the Warning Letter. The response should include specific actions for any identified violation, from developing new SOPs to monitoring by the quality control unit. Be careful not to promise more than you can deliver. FDA takes corrective and preventive action plan implementation very seriously. If you have questions about violations, contact the FDA District Office for additional information, or request a meeting with FDA. Submit a response within the identified timeframe, typically 15 days. 

3. Of utmost importance to FDA is that a company demonstrates an acknowledgement of the seriousness of the observed violations, a reasonable sense of urgency (with specified target dates), and that corrective actions clearly prove (with data or evidence where possible) that the compliance issue has been resolved.  

Standard operating procedures, whether developed to meet regulatory compliance or to reinforce corporate policies, are critical to efficient operations, quality control, and regulatory compliance. When properly designed, distributed, and tested, they provide employees with practical, understandable information that enable safe and efficient job performance. When properly managed and monitored, SOPs equip employers with a clear view of existing knowledge gaps and potential inefficiencies caused by inadequate training. And, for any company on the receiving end of a 483 or Warning Letter, they represent an opportunity to achieve compliance and improve operational efficiency—simultaneously. 

SOPs are written job aids that detail the procedure of how to do a specific job task correctly.

Assuring the Effective Use of Standard Operating Procedures (SOPs) In Today's Workforce

Today's global marketplace challenges the pharmaceutical industry to deliver quality medicines to patients under a fractured regulatory environment. Managing regulations, inspections, approvals, and other requirements can be overwhelming. Recently released guidance documents from the International Conference on Harmonization (ICH), which are based on solid scientific principles, have the potential to simplify the drug registration process.  

For example, at the Parenteral Drug Association (PDA) meeting in Paris in December 2004, Dr. Emer Cooke, head of the EMEA Inspectorate, remarked, "Risk concept is mentioned 90 times and in 20 documents in EU GMP legislation and guidance."

  Cooke cited the phrase "unless otherwise justified" as direct linkage to Quality Risk Management. In other words, current regulations support good science. In addition, greater emphasis is being placed on guidances based on international harmonization. This article focuses on the most recent quality guidances developed by the International Conference on Harmonization (ICH), both finalized: ICH Q8, 

, is under development. These documents realize the consensus vision statement developed and adopted by all parties and observers involved at the ICH meeting in Brussels in July 2003: 

Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product, emphasizing an integrated approach to quality risk management and science.

ICH is an organization that includes regulatory and industry representatives from Japan, the United States, and the European Union. ICH operates by consensus; the underlying goal is to apply good scientific principles to pharmaceutical regulation. Canada, along with other countries and the World Health Organization, has observer status in ICH; however, this involvement has not prevented these countries from developing their own guidances that conflict with those of ICH.  

The work to date on the above-mentioned trio of documents has been extraordinary. The scope of the work was first envisioned as a harmonized quality system describing a life cycle approach. Now we are at the stage when we are beginning to realize the benefits of two of the three documents. With the anticipated addition of Q10, the entire suite of documents will provide the basis for the full benefits to be realized. 

 was originally intended to provide details of the expected content for the subsections of section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of module 3 of the Common Technical Document (ICH guideline M4). This part of ICH Q8, 

 is logical, educational, and didactic. Embedded within the document is a gem of a concept: 

. These two words and their associated definition have started a minor revolution in our industry. Here is the definition excerpted from the document: 

Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters demonstrated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval."

The definition of design space takes into account raw materials, components used in processes, operating parameters of equipment, and the interactions among them. It also implies the need to carry out a rigorous, science- and risk-based approach (based on ICH Q9) to development studies. Carefully chosen words such as "working within the design space" start to lay the groundwork for firms who invest in understanding their processes to manage continual improvements within their own quality systems. The overall principle, the extent of knowledge obtained by the firm and shared with the regulator, defines the extent of a flexible regulatory approach applied to affecting changes without prior regulatory approval. 

The concepts embedded in Q8 transcend its application solely to drug products. Most of the comments to the docket for the version posted as FDA guidance suggested expanding the applicability towards drug substances and larger molecules. ICH Q8 is now being revised to clarify its revolutionary concepts. Discussions are under way within ICH about extending the concepts to active pharmaceutical ingredient (API) development, including both new chemical entities and biotechnology drug substances.  

Q9 is the repository for the risk-management tools to be applied both in Q8 and Q10. John Berridge, who is vice president for Pfizer Global Research and Development and the rapporteur for the initial stages of Q8 and now its revision, described Q9 as a collection of tools, drawing the comparison between wrenches, pliers and hammers, which can be used, per the guidance,  to put a car together (development) or to maintain a car (commercial manufacturing). Risk Management tools are commonly used in many other industries, most notably the insurance industry, to analyze, evaluate, and manage risks. The guidance describes examples of how to apply the tools to a variety of pharmaceutical systems.  

When first faced with implementing Quality Risk Management, one could become paralyzed with indecision about which tool to use in a given application. Unlike statistical analysis, where it is necessary to understand the data (normality, randomness), in quality risk management there is no wrong tool to use, since there are no statistical rules to violate. The correct tool is the one the user feels most comfortable with. In the total absence of experience, one can look at other applications of Quality Risk Management. For example, a recent FDA white paper, which discusses applying risk management to determining inspectional priorities, is an excellent example of risk ranking and filtering.

The concept of design space has started a minor revolution in our industry.

BioPharm International-09-02-2006

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

Expediting the Technical Transfer of Biopharmaceutical Products

Writing Effective Development Reports

Assuring the Effective Use of Standard Operating Procedures (SOPs) In Today's Workforce

Achieving Global Consensus through the International Conference on Harmonization

The Laboratory Control System: Fulfilling cGMP Requirements

Asset Management for Growing Biotech Companies