Compliance by Design and Compliance Master Plan

The US pharmaceutical industry has experienced great advancements in development and control of manufacturing processes in the recent past. The quality-by-design (QbD) effort has transformed new product development, resulting in more sophisticated development and manufacturing approaches. Implementation of modern technology that is now commonplace in the pharmaceutical manufacturing environment has been facilitated by QbD. While celebrating QbD technical process advancements, the industry has simultaneously experienced several negative well-publicized events, mainly regarding issues with the supply chain and contamination of products—all deficiencies in compliance. These events were not caused by manufacturing process problems but rather by deficiencies in compliance. Some events were caused by deliberate criminal actions, such as economically motivated adulteration (e.g., the heparin substitution by oversulfated chondroitin sulfate in 2008). Other problems, however, were preventable (e.g., the Viracept cleaning in 2006, in Germany) and certain business factors (e.g., inexperienced and reduced headcount) may have contributed to these situations.

Basis for approach

The proposed approach to quality systems and compliance throughout the entire drug product life cycle includes the new concepts of compliance by design (CbD) and a compliance master plan (CMP). This organized approach is based on the following:

Quality by design. Key aspects of QbD include the quality target product profile (QTPP), critical quality attributes (CQAs), formulation and process design and development, critical process parameters (CPPs), critical material attributes for drug substance and excipients, risk assessment, design space, scale up, and control strategy (1). The product and manufacturing process is continually monitored and updated to ensure consistent quality during the product's commercial life cycle. Changes and continuing improvements in product and process are expected.

Life-cycle approach to process validation. The life-cycle approach to process validation has significantly expanded the focus of validation to include product design and development through postvalidation monitoring. The life-cycle approach to process validation guidance has been discussed for more than five years and was finalized by FDA in January 2011 (2). The three stages of the life-cycle approach to process validation include process design, process qualification, and continuous process verification.

Validation master plan. The validation master plan (VMP) is a well-accepted document in pharmaceutical manufacturing (3–5). Auditors almost always request the VMP in regulatory audits.

Compliance by design

Applications of the QbD approach to pharmaceutical development and manufacturing can be fundamentally conceptualized and simplified for application to quality systems as follows:

CbD design and objectives. The CbD design and objectives provide comprehensive expectations and critical attributes for a quality system. Just as a QTPP and CQAs are determined for a product being developed, compliance objectives and attributes are determined for a quality system. When implementing this approach, one might ask, Is the system appropriately designed to accomplish quality system objectives?

CbD critical parameters. The CbD critical compliance parameters are essential activities to ensuring that systems objectives and quality attributes are accomplished. Just as CPPs directly affect the CQAs of a product, crucial compliance parameters may affect the accomplishment of attributes for the quality system. What parameters may affect successful accomplishment of objectives?

CbD input variation and control. The CbD input variable control strategy identifies potential changes or variables that might affect the quality system and provides a proactive method for their control.

CbD ongoing maintenance and management. CbD ongoing monitoring and maintenance activities contribute to continuing the success of the quality system. What will be monitored to maintain successful system performance to meet objectives?

Process analytical technology (PAT) and risk analysis. Just as PAT is recommended for real-time process control and minimizing variation, similar technology should be implemented as appropriate for quality systems applications. For instance, real-time monitoring and control of a warehouse would be a practical application, especially for areas where temperature-sensitive products are stored. Priority for implementation should be assigned to the highest risk applications.

Life-cycle approach to quality systems

The application of the process validation life-cycle approach to pharmaceutical quality systems and compliance is proposed. Application of the life-cycle approach causes a comprehensive and continuing approach to quality systems. Quality systems must be properly designed to accomplish system objectives. After satisfactory establishment and ongoing operation of the system, performance should be appropriately monitored and evaluated. Corrections and improvements should be initiated as indicated. Execution and compliance in quality systems must not be static and should be continually improved.

Table I: Compliance master plan strategy and approach.

Compliance master plans

It is proposed that documentation of the CbD program be contained in a compliance master plan (CMP). The CMP is analogous to the current and well-accepted VMP. The concept of a CMP has been suggested by Nash (6) based on the work of Borkar (7). These authors proposed that six quality systems and 26 quality-system elements form the basis for a CMP. Table I provides an example CMP table of contents indicating section titles according to a quality-systems structure (8). Table II describes the specific content of a chapter discussing a quality system using the CbD general concept.

Table II: Compliance by design and compliance master plan quality system chapter content.

Why implement CbD and CMP?

The following are potential benefits to implementing the CbD and CMP approach to quality systems and compliance:

• Organized and comprehensive focus on quality systems and compliance: Objectives, key attributes, successful performance, and improvement commitments should be clearly defined.

• Cross-functional thinking: The CbD approach to quality systems should break down organizational barriers and ensure consistent compliance objectives, attributes, risk assessments, and so forth, between functional areas.

• Consistent prioritized mitigation activities across functions: CbD should potentially facilitate consistent focus on high-risk activities and mitigation of high-risk problems.

• Proactive variation identification and control strategy: CbD requires prospective consideration of potential input variation and development of a control strategy to minimize potential compliance issues.

• Standardized audit expectations and documentation: Maintaining the CMP, including project commitment dates, keeps the organization in a continuing state of readiness for regulatory and other audits.

• Centralized tracking of commitments: The CMP document centralizes all commitments and should serve as the primary resource for tracking information in the same manner as the VMP.

• Organization commitment, transparency, and credibility: Implementing a CbD and CMP approach should facilitate organizational transparency regarding compliance, foster accountability, and increase the credibility of the compliance effort with auditors and with employees who do the work of compliance.

Implementation strategy and approach

The CbD-approach proposal may be implemented by building on current quality-systems programs and VMP content that already exists at the manufacturing site. FDA has been auditing according to the quality systems approach for several years. Industry may already have functional structures and documents organized according to quality systems such as validation and the VMP.

Identification of major quality systems. Using the six FDA quality systems as a starting point, all the distinct quality systems in the organization should be specified. For example, validation, product stability, and annual product-review programs are currently listed under the FDA Quality System. These may be separated as individual quality systems for administration by the CbD approach. Programs that support multiple quality systems might also be specifically separated. For example, training is mentioned in all FDA quality systems. A separate training quality system could be specified under the CbD approach.

Analysis of each individual system. After all individual systems (e.g., stability system, training system) are identified, each is analyzed and evaluated. The following actions would be performed on the individual system:

• Identify the complete business process for the system: These may be relatively complex with multiple individual functions with global components, or they may be less complex, such as the training system with a centralized function and direct involvement with all functional areas in a facility.

• Identify system subsections: After the business process is identified, logical subsections can be determined that represent distinct groups of activities within the quality system. These may be individual departments within the organization. Identify objectives, critical compliance attributes, CPPs, variation, controls, and maintenance for all subsections.

Gap analysis for each individual system and subsystem. Identify any gaps in subsections and initiate corrective action. Procedures should be available for all significant activities in each subsystem. If needed, a commitment to develop new procedures should be made. Management, staff, and the quality assurance (QA) department should conduct this analysis with cross-functional input. Staff participation and cross-functional input is critical for the success of the analysis. Process experience, vendor audits, product data, deviations, corrective action and preventive action (CAPA), and other sources of information should be used to identify gaps or problem areas.

Risk analysis. Subsections are evaluated with regard to risk. If procedures are not appropriate for high-risk activities, they should be appropriately enhanced. Conversely, attention to lower-risk areas may be appropriately reduced. Risk to the patient, the process, and the organization (i.e., business risk) should be considered.

Continuous improvements. Continuous-improvement projects based on gap analysis, risk analysis, and system performance should be identified.

Performance measurement. Performance measurement parameters should be identified, monitored, and trended as appropriate. Corrective actions should be initiated as appropriate. Improvement projects should also be initiated as appropriate.

Documentation. All of these implementation strategies should be documented in the CMP.

A CbD example: materials system business process

This section provides a high-level description of the steps involved in the business process for the materials quality system in a pharmaceutical manufacturing facility.

• Step 1: Identify approved vendors to source incoming materials (the vendor QA department audits potential suppliers and approves vendors)

• Step 2: Incoming materials are received at manufacturing site.

• Step 3: Incoming materials stored in pharmaceutical warehouse–quarantine status.

• Step 4: Sample incoming materials based on defined sampling plan.

• Step 5: Submit incoming materials for testing

• Step 6: Receive and evaluate test results

• Step 7: Transfer tested materials to appropriate status areas (at this stage, materials will be approved or rejected, with materials on test remaining in quarantine and rejected materials destroyed or returned to the supplier)

• Step 8: Purified water, steam, nitrogen, and compressed air available in manufacturing area.

• Step 9: Sample purified water, nitrogen, and compressed air based on defined sampling plan

• Step 10: Receive and evaluate test results

• Step 11: Dispense approved incoming materials to manufacturing areas

• Step 12: Receive and store manufactured and finished products–quarantine status.

• Step 13: Store tested materials in status areas (at this stage, materials on test are approved or rejected, with materials on test remaining in quarantine and rejected materials returned to manufacturing for rework or destroyed)

• Step 14: Transfer approved materials to distribution center

• Step 15: Ship approved materials from distribution center to customer.

Materials system subsections. After the business process is completed, appropriate subsections can be identified. For example, the materials system may include the following distinct subsystems:

• Incoming materials—sourcing (Step 1)

• Incoming materials—receipt and storage (Steps 2–7)

• Purified water and compressed gases–material maintenance (Steps 8–10)

• Dispensing—for future manufacturing (Step 11)

• Finished products—storage (Steps 12–13)

• Finished products—distribution (Steps 14–15).

Materials system subsections are illustrated in Table III. Detailed business processes should be specified for all subsections.

Table III: Materials system subsections (A is approved, R is rejected, Q is quarantine).

Subsection analysis and evaluation. Each materials system subsection should be described and analyzed regarding objectives and successful system attributes. Critical activities, potential variation affecting performance, and related factors should be identified, and a detailed business process should be developed for each subsection. Gaps and improvement projects may be identified as well, and a CAPA project may be committed based on risk. Adequacy of procedures should be reviewed. Table IV describes the sourcing subsection of the materials quality system. This analysis should be completed for all identified subsections within the quality system.

Table IV: Materials system-sourcing subsection.

Performance measurement. Methods to quantify and document the performance of the respective subsections are identified. For example, this would include compiling and reviewing quality audits and vendors, obtaining and reviewing test results of all materials from individual vendors are reviewed, monitoring lag time between order and receipt of materials, tracking and trending test data for high-risk incoming materials, reviewing drug dispensing errors for dispensing technicians; and reviewing time delays between material request and material dispensing. Each of these actions is part of ensuring quality system performance.

CMP documentation. All of the business processes and subsections should be documented in the materials system section of the CMP. Table V generally describes the materials system chapter in the CMP. This chapter could be updated as needed to maintain usefulness (i.e., a site having frequent audits might choose to update the CMP every quarter, while other sites may update on an annual basis).

Table V: Compliance master plan-materials system components.

The practicalities of CbD implementation

The decision to implement a CbD program in a manufacturing site is a major decision. Significant commitment including self-inspection of functional areas is involved. Self-inspection may be painful depending on the status of the area. Success in implementing a new program often lies in the approach to implementation; it is not the same as installation of equipment. Personnel are involved, and attitudes may need to change.

To successfully implement CbD (9), one needs to first obtain management commitment. Management must demonstrate that implementation of the CbD approach is not just another "buzzword" program, but rather, a real approach to improving compliance.

Second, a company might consider a pilot program. Select a single section within a quality system to initiate the program, and select a "stand-alone" function having minimal complex interactions. Clearly define the scope, objectives, and criteria for measuring success. For example, select a single laboratory within the analytical function, or select the annual product review group that accesses data and prepares reports.

Third, be sure to involve only interested people or, minimally, people with an open mind as to the value of the change. This third implementation strategy includes the following:

• Train only those involved on the program

• Listen to the feedback and suggestions of those involved, including making adjustments and improvements as necessary

• Expect mistakes and problems and learn from those mistakes

• Conduct periodic review sessions to monitor progress, make adjustments, and listen to participants

• Celebrate successes

• Add new areas to be implemented as success is proven with prior areas

• Include and train new personnel as success is demonstrated and the program expands

• Incorporate the CbD and CMP system into the company culture, including making the program the normal way of doing business.

When implementing a QbD program, companies should be careful to avoid implementing multiple systems or the entire program all at once. Training should be initially limited to only those personnel directly involved with the program. Participation of personnel should be based on interest and should not be forced upon those personnel that may oppose change. Reasonable deadlines should be set, and the program should be given time to be implemented. In other words, do not terminate the project at the first sign of failure.

Conclusion

The CbD approach provides an organized and focused approach to quality systems and compliance based on proven successful and acceptable methods. This approach should facilitate a proactive evaluation of compliance performance against compliance attribute standards. Implementation should provide multiple benefits to the organization. An organization that embraces the CbD approach demonstrates a strong commitment to current good manufacturing practice compliance and increases the credibility of the compliance effort with auditors.

Paul L. Pluta, PhD,* is a an adjunct associate professor at the University of Illinois at Chicago College of Pharmacy in Chicago, IL, and editor-in-chief of the Journal of Validation Technology and the Journal of GXP Compliance, published by Advanstar Communications, paul.pluta@comcast.net. Richard Poska is director of Abbott Pharmaceutical Products Group Regulatory Affairs at Abbott, Abbott Park, IL. Timothy J. Fields is senior director of quality operations at the Protein Sciences Corporation, Meriden, CT.

References

1. L. Yu et al., Pharm. Technol. 33 (9), 122–127 (2009).

2. FDA, Guidance for Industry, Process Validation: General Principles Practices (Rockville, MD, January 2011).

3. T. Miller, J. Validat. Technol., 14 (5), 10–13 (Autum 2008).

4. M. Gladfelter, J. Validat. Technol. 15 (1), 16–22 (Winter 2009).

5. J. Pawlik, J. Validat. Technol. 15 (2), 63–67 (Spring 2009).

6. R. Nash, J. Validat. Technol. 12 (2), 86–90 (February 2006).

7. M.M. Borkar, A. A. Shirwaikar, and P.G. Shilotri, J. GXP Compliance 9 (2), 144-153 (January 2005).

8. FDA, Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations (Rockville, MD, September 2006).

9. L. Torbeck, J. GXP Compliance 15 (1), 13–15 (Winter 2011).

*Part one of this commentary, "Compliance by Design (CbD) and Compliance Master Plan (CMP)–An Organized Approach to Compliance," was published in the Journal of GXP Compliance 14 (2), Spring 2010.