Keep in Step with Confidence; Keep in Step through Benchmarking

The Journal of Validation Technology (JVT) is pleased to provide an interactive feature that is becoming a valuable resource to all involved in various types of process validation.

This feature, "Benchmarking," under the leadership of Paul L. Pluta, Ph.D., contains responses to questions posed to JVT readers on timely topics in various process validations.

This forum provides discussion on current industry practices on questions of interest. Enabling readers to determine best practices in validation is the ultimate objective of these discussions.

Questions are presented for discussion in each issue of JVT. Reader responses are anonymously summarized and reported in subsequent issues. The anonymity of all respondents is guaranteed, unless otherwise requested.

Please provide your comments to questions for inclusion. Simply click "REPLY NOW" button after each question and respond, or send an email to the Coordinating Editor shaigney@advanstar.com with your response. Suggestions for new questions for discussion in future issues of JVT are also requested.

FDA Guidance for Industry. Powder Blends and Finished Dosage Units -- Stratified In-Process Dosage Unit Sampling and Assessment (Draft). FDA, October 2003.

2. PROCESS VALIDATION PARTICLE SIZE PROFILE SPECIFICATIONS

The 1994 FDA Guide to Inspections of Oral Solid Dosage Forms; Pre / Post Approval Issues for Development and Validation recommended the particle size profile of granulations as an important physical parameter to demonstrate equivalence between batches. Acceptance criteria for particle size profile distributions may be approached in different ways; for example:

Not more than ___% of granulation smaller than 60 mesh

• Mean particle size between ___ (low) microns and ___ (high) microns

• Not more than ___% of granulation larger than 10 mesh, and not more than ___% smaller than 80 mesh.

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Guide to Inspections. Oral Solid Dosage Forms. Pre / Post Approval Issues for Development and Validation. FDA, January 1994.

Question: What are approaches to validation specifications or validation acceptance criteria for particle size distributions of granulations?

Responses to this question cautioned against specifications implemented prior to determination of true process variation, i.e., a sufficient number of lots must be manufactured and characterized to determine true process variation. Also, particle size distributions may expectedly change with use of new vendors.
Several approaches to specifications were proposed as follows:

• Statistical difference in particle size between starting materials and the blended granulation. Average particle size was determined by summation of percentages on screens x screen pore size.

• Specifications limiting the amount of course particle size and fine particle size extremes.

• Defined percentage ranges for multiple particle size fractions which fully characterize the lot particle size distribution; an example with four particle size ranges was provided.

Additional discussion of responses was reported in JVT 11, #4 (August 2005). Discussions in JVT and on the website will be updated as new responses are received.

3. CLEANING VALIDATION ANALYTICAL RECOVERY STUDIES

Recovery studies on materials of product contact for cleaning validation are conducted to assure the ability to detect cleaning residues by swab or rinse sampling. Large manufacturing facilities with multiple equipment types may have many different materials of product contact. Each material may also have different grades, surface finishes, fabricating processes, and other variations. For example, there are multiple types of stainless steel, coatings on aluminum, and types of non-metallic polymers / plastics commonly used in pharmaceutical processing equipment. In Special Edition: Cleaning Validation III (IVT), Thomas utilized 316L stainless steel, polyethylene, and silicone as representative materials for cleaning validation recovery studies. Jin and Woodward utilized stainless steel, Delrin, Nylon, Lexan, and glass in detergent recovery studies.
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Perry, Robert H., Don W. Green, and James O. Maloney. Perry's Chemical Engineers' Handbook, 7th edition, McGraw-Hill, New York, 1997.

Thomas, Julie A. A Cleaning Validation Master Plan for Oral Solid Dose Pharmaceutical Manufacturing Equipment. Special Edition: Cleaning Validation III. Institute of Validation Technology.

Jin, James G. and Cheryl Woodward. Development of Total Organic Carbon (TOC) Analytis for Detergent Residue Verification. Special Edition: Cleaning Validation III. Institute of Validation Technology.

Question: What are approaches to analytical recovery studies for cleaning validation that will encompass the wide varieties of materials, grades of materials, surface finishes, and other material variations typical of large manufacturing facilities?

Responses indicated that similar materials are grouped for recovery studies. For example, 316 stainless steel is used to represent all grades of stainless steel for reasons of widespread use of 316 stainless steel in pharmaceutical process equipment. Respondents provided specific examples of inappropriate grouping. Additional discussion of responses was reported in JVT 11, #4 (August 2005). Discussions in JVT and on the website will be updated as new responses are received.

4. PROCESS VALIDATION OF FINISHED DOSAGE UNITS

The 2003 FDA Guidance Powder Blends and Finished Dosage Units – Stratified In-Process Dosage Unit Sampling and Assessment proposed twenty samples to be withdrawn during dosage form manufacturing of the lot; testing conducted for this sampling is for dose uniformity. Other tests for quality attributes may also be conducted during sampling at this stage of manufacturing. For example, tests such as dissolution, moisture, degradants, and other attributes are tested.
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FDA Guidance for Industry. Powder Blends and Finished Dosage Units -- Stratified In-Process Dosage Unit Sampling and Assessment (Draft). FDA, October 2003.

Question: What are approaches to testing of attributes other than dose uniformity in extended continuous processes (i.e., compressing, encapsulation) in pharmaceutical manufacturing? How is sampling conducted for specifications such as dissolution, moisture, and degradents? For example, sampling for dissolution may be conducted at beginning, middle, and end of the process.

Responses to this question were grouped into two different approaches as follows:

• Conduct multiple Quality Assurance tests routinely conducted in commercial product manufacturing when executing Process Validation, following the basic tenet that validation testing should exceed and support testing conducted for routine commercial product manufacturing.

• Evaluating quality attributes in terms of importance to the product and testing appropriately. This approach is product-specific and would require individualized testing depending on the product being validated.

Additional discussion of responses was reported in JVT 12, #1 (November 2005). Discussions in JVT and on the website will be updated as new responses are received.

5. PROCESS VALIDATION OF NEW OR CHANGED MATERIALS

Material changes are common occurrences in pharmaceutical manufacturing. New vendors providing chemically same material, new processes to manufacture "same" material, new manufacturing sites with "same" process, new equipment for "same" process, new cleaning agent composition with "same" cleaning performance, and other variations must be validated. These changes are applicable to manufacturing, cleaning, and packaging validation.

Question: What are approaches to evaluation of changes for determining extent of work (number of lots, number of samples, etc.) for validation?

Responses to this questioned focused on manufacturer information and laboratory studies to determine the extent of differences between the original and new materials. Functionality differences between new and current material was discussed. The importance of quality agreements and communication between supplier and manufacturer regarding communication of changes is critical. Additional discussion of responses was reported in JVT 12, #1 (November 2005). Discussions in JVT and on the website will be updated as new responses are received.

6. CLEANING VALIDATION PRODUCT CONTACT MATERIAL SAMPLING.

Process trains may comprise a significant variety and number of product contact materials. Manufacturing process trains are usually primarily stainless steel; they may also comprise cast iron, bronze, brass, anodized aluminum, polymer-coated aluminum, various multiple plastics, gaskets, o-rings, various multiple fabrics, and other materials. It is desirable to sample as many of these materials as possible in cleaning validation. However, some materials may be physically too small or of unusual geometry to be able to sample; the percent contribution of these materials to the total process train surface area may be very small. Firms may decide that materials whose contribution to the process train total surface area is less than X% will not be tested in cleaning validation.

Question: What are approaches to evaluation product contact materials for sampling? Is there a minimum percentage at which materials are not sampled? Are acceptance criteria for materials that are sampled adjusted (lowered) to compensate for not sampling all materials?

Responses to this question were grouped into two different approaches as follows:

• Conduct sampling on all product contact materials that exceed a minimum percent contribution to the total process train surface area.

• Conduct sampling on all materials based on a worst-case approach, i.e., difficult to clean locations in equipment. No materials are excluded from evaluation.

The method of Fourman and Mullen or 10 ppm critieria in subsequent product was used to calculate acceptance criteria for residue limits. Additional discussion of responses was reported in JVT 12, #1 (November 2005). Discussions in JVT and on the website will be updated as new responses are received.

7. PROBLEMS WITH PROCESS VALIDATION -- MANUFACTURING PROCESS VALDATION

In "Understanding Validation Requirements: An FDA Perspective," (presented by Lori Lawless), Indicators of Non-Validated State, Common Validation Problems, and Underlying Problems in process validation were identified. Examples from these lists included repeated product failures and in-process test result failures, and inadequate control of vendors. These comments provide valuable insight to practitioners in manufacturing process validation.
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Lawless, Lori. "Understanding Validation Requirements: An FDA Perspective." Journal of Validation Technology, Volume 11, Number 3, 25-259, May 2005.

Question: What are the major problems experienced in practice of manufacturing process validation?

Responses were grouped into general problems and specific problems as follows:

• General problems include lack of general understanding of validation principles such as the confirmatory aspects of validation, technical aspects of validation, and validation documentation.

• Specific problems including determination of appropriate testing and sampling, general execution of validation, and change control.

Additional discussion of responses was reported in JVT 12, #2 (February 2006) and JVT 12, #3 (May 2006). Discussions in JVT and on the website will be updated as new responses are received.

8. PROBLEMS WITH PROCESS VALIDATION -- CLEANING PROCESS VALDATION

Papers recently published in the Journal of Validation Technology have identified problems with various aspects of validation. In "Road Map for Equipment Cleaning Validation Within a Multi-Products manufacturing Facility," Jose A. Morales Sanchez identified ten most common errors in his experience associated with cleaning validation. Two examples from the list of ten most common errors included: Failing to train operators well and failure to instill a sense of high commitment; and not having an adequate cleaning monitoring system. These comments provide valuable practical insight to practitioners in cleaning validation.
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Morales Sanchez, Jose A. "Road Map for Equipment Cleaning Validation Within a Multi-Products Manufacturing Facility." Journal of Validation Technology, Volume 11, Number 3, 216-224, May 2005.

Question: What are the major problems experienced in practice of cleaning validation?

Responses were grouped into general problems and specific problems as follows:

• General problems include lack of general understanding of validation principles such as the confirmatory aspects of validation, technical aspects of validation, and validation documentation.

• Specific problems including analyte selection, cleaning agent selection, parameter control in manual cleaning, importance of non-uniform contamination, and testing of low percent surface area materials.

Additional discussion of responses was reported in JVT 12, #2 (February 2006), JVT 12, #3 (May 2006), and JVT 12, #4 (August 2006). Discussions in JVT and on the website will be updated as new responses are received.

9. PROBLEMS WITH PROCESS VALIDATION -- PACKAGING PROCESS VALDATION

Question: What are the major problems experienced in practice of packaging process validation?

Responses were grouped into general problems and specific problems as follows:

• General problems include lack of general understanding of validation principles such as the confirmatory aspects of validation, technical aspects of validation, and validation documentation.

• Specific problems including process approach vs. or equipment approach to package validation.

Additional discussion of responses was reported in JVT 12, #2 (February 2006). Discussions in JVT and on the website will be updated as new responses are received.

10. PROBLEMS WITH PROCESS VALIDATION CHANGE CONTROL -- MANUFACTURING PROCESS VALDATION, CLEANING PROCESS VALIDATION, PACKAGING PROCESS VALIDATION.

One of the validation problems identified in responses to the questions discussed above included change control and impact of change on the validated process. There are many possible changes in pharmaceutical manufacturing potentially affecting a validated process. These may range from active drug and excipient incoming material changes such as new suppliers or manufacturing process changes in excipient manufacturing; equipment changes such as new / more efficient equipment or increased capacity equipment for larger batch sizes; process changes such as those associated with implementation of process analytical technology; and cleaning agent changes such as elimination of phosphate from a proprietary formulated cleaning agent.

The various FDA SUPAC Guidances are valuable resources in helping to categorize change and providing guidance as to the appropriate level of testing associated with formulation equipment and process changes. The respective Manufacturing Equipment Addendums to the SUPAC Guidances are also helpful in categorizing manufacturing equipment according to operational principles.
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Guidance for Industry. Immediate Release Solid Oral Dosage Forms. Scale-up and Post-approval Changes: Chemistry, Manufacturing, Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation. FDA, November 1995.

Guidance for Industry. SUPAC-IR / MR: Immediate Release and Modified Release Solid Oral Dosage Forms. Manufacturing Equipment Addendum. Revision 1. FDA, January 1999.

Guidance for Industry. SUPAC-SS: Nonsterile Semisolid Dosage Forms. Manufacturing Equipment Addendum. Draft Guidance. FDA, December 1998.

Question: What are the major problems experienced in change control regarding the respective types of process validation?

Responses to this question were categorized into three groups. These included:

• Recognition of change, i.e., is the change executed really a "change," or was it a "like for like"? Personnel making changes are not aware that the change needs to be adequately described, evaluated, documented, and ramifications addressed. Activities associated with an example change were discussed.

• Evaluation of the criticality of the change; how much evaluation is appropriate. Respondents described evaluation approaches from relatively simple "Major-minor" categories of change to more complex FMEA (Failure Mode Effects Analysis) systems. Criticality determination must be documented.

• Documentation. Adequacy of documentation including appropriate level of discussion and supportive documentation was discussed.

Additional discussion of responses was reported in JVT 12, #4 (August 2006). Discussions in JVT and on the website will be updated as new responses are received.

11. PROCESS VALIDATION OF TABLET COMPRESSING

The process validation of tablet compression processes is accomplished by testing quality attributes such as content uniformity, dissolution, moisture, and other attributes from stratified sampling conducted throughout the process. Machine operating parameters may vary between lots; example parameters include pre-compressing force, main compressing force, and turret speed. After appropriate set-up of operating parameters, in-process testing or machine control of tablet weight, thickness, and hardness maintains compressing at target attributes by adjusting machine parameters.

Question: How are ranges of operating parameters such as compressing forces and turret speeds handled in process validation? Are separate runs at high and low parameter extremes conducted to validate ranges of parameters? Or are multiple runs at the same parameter settings conducted to demonstrate repeatability? Any other options?

12. PROCESS VALIDATION OF TABLET COATING

The process validation of tablet coating processes is accomplished by testing quality attributes such as tablet weight, dissolution, physical appearance, and other attributes from coating runs. Machine operating parameters may vary between lots; most variation is observed in individual coating run batch size. Coating batch size depends on the yield of compressed tablets. The coating batch size may significantly influence coating performance in perforated pan coaters in which air flow through the tablet bed is an important operating parameter.

Question: How are batch size ranges of individual coating runs validated? Are separate runs at high and low batch size extremes conducted to validate coating batch size ranges? Is an arbitrary batch size range, e.g., +/-10%, considered acceptable without specific batch size testing? Any other options?

13. CLEANING VALIDATION ANALYTICAL UNKNOWN PEAKS

Cleaning validation requires demonstration that equipment is visually clean and that active drug and cleaning agent residues determined by analytical testing are below calculated acceptable limits. These limits are based on drug dosage or toxicity. Regarding analytical testing of drug residues using specific analytical method (e.g., HPLC), the chromatogram may indicate absence of active drug residue demonstrating acceptable cleaning of active drug. However, other peaks (i.e., unknown peaks) at significant levels may be noted in the chromatogram. These peaks indicate the presence of other residue in the sample.

Question: How are HPLC unknown peaks handled in cleaning validation?

14. CLEANING VALIDATION SAMPLING

The validation of cleaning processes is usually accomplished by cleaning equipment according to procedures, evaluating visual cleanliness, and evaluation of residual active – drug, degradants, or cleaning agent – residues vs. calculated acceptance criteria. Multiple equipment in the process train are usually sampled. A process train may comprise as many as ten different major pieces of equipment.

Question: How many samples are needed to adequately validate a cleaning process? Are all major pieces of equipment sampled, or only worst-case equipment?

15. PROCESS VALIDATION OF SOLID MIXING or BLENDING PROCESSES

Sampling for powder blends and finished dosage units were recommended in the October 2003 FDA Draft Guidance and associated Product Quality Research Institute (PQRI) document. This testing is the final blend testing prior to manufacture of the final dosage form. Mixing prior to granulation or other intermediate mixing is not addressed in this guidance.

Question: Are mixing processes prior to final formulation mixing or blending tested for blend uniformity? For example, is mixing before wet granulation tested to determine blend uniformity to validate mixing before wet granulating?

16. PROCESS VALIDATION OF LIQUID or SEMISOLID MIXING PROCESSES

The typical manufacturing of liquid or semisolid dosage forms comprises mixing of the formulation in a mixing vessel, followed by filling into commercial containers. This process is utilized for solutions, suspensions, lotions, semisolids (ointments and creams), suppositories, and similar dosage forms.

Question: How many samples are appropriate to validate liquid mixing processes?

17.WORST-CASE PRODUCTS FOR CLEANING VALIDATION

Manufacturing plants that process multiple formulations may use a matrix approach for cleaning validation. This approach defines product groups, and then validates the cleaning process for the worst-case product in the group. Cleaning of all products in the group is then considered to be validated.

Question: How are worst-case products for a cleaning validation matrix approach determined?

18.WORST-CASE LOCATIONS FOR CLEANING VALIDATION SWAB SAMPLING

Comments on Question 14, above, prompted reader requests for benchmarking of approaches and considerations to determine worst-case locations for cleaning validation sampling.

Question: How are worst-case locations for cleaning validation swab sampling determined?

19. PROCESS VALIDATION OF FINAL BLENDING PROCESSES

The 2003 FDA draft guidance for powder blends and finished dosage units recommends at least ten samples of the powder blend to demonstrate adequacy of the blending process. These results are then compared to individual dosage form data from stratified samples during the unit dosing process. The 1994 FDA guide to oral solid dosage form development and validation mentions granulation studies to include blend uniformity, sieve analysis, and moisture as important in-process testing and part of granulation analysis in demonstration (validation) runs.

Question: What testing is conducted to validate solids final blending processes?

20. CLEANING VALIDATION EQUIPMENT HOLD TIME BEFORE CLEANING (DIRTY HOLD TIME)

The 1993 FDA document on cleaning validation commented that identifying and controlling the length of time between the end of processing and each cleaning step was an often critical element in cleaning documentation. Topicals, suspensions, and bulk drug operations were specifically mentioned regarding drying of residues directly affecting the efficiency of a cleaning process. LeBlanc has also addressed approaches to equipment dirty hold time in multiple references.

Question: How is equipment hold time before cleaning (dirty hold time) addressed in cleaning validation? Are three lots tested at the worst-case equipment dirty hold time, or is only one lot (of the three validation lots) tested at the worst-case time limit?

21. MANUFACTURING PROCESS VALIDATION OF NON-STANDARD BATCH SIZES

Manufacturing of non-standard batch sizes may occur for multiple reasons. Non-standard batch sizes may be intentional, i.e., increasing or decreasing market demand may necessitate a new batch size for a product. Non-standard batch sizes may also be unintentional. For example, an unexpected loss of process material during processing could necessitate non-standard processing.

Question: What are considerations for the process validation of non-standard batch sizes?

22. EQUIPMENT INFORMATION FOR CLEANING VALIDATION

There is fundamental information on processing equipment that must be compiled in support of the various aspects of cleaning validation. This information is most easily obtained from the equipment manufacturer, and then documented in the equipment installation qualification (IQ). This information is useful for cleaning procedure development, compatibility with cleaning agents, residue level calculations, equipment grouping, and other applications. Equipment grouping is desirable to reduce the number of replicate runs to demonstrate cleaning validation. A clear definition of required information is useful when purchasing new equipment.

Question: What information on processing equipment is needed in support of cleaning and cleaning validation?

23. TABLET COATING PROCESS VALIDATION TESTING AND SAMPLING

The process validation of tablet coating processes is accomplished by testing quality attributes, such as tablet potency, dissolution, physical appearance, and other attributes from coating runs as described in the product specifications. There may be other non-specification testing conducted to validate the coating process.

Question: What is appropriate testing and sampling for process validation of tablet coating processes ?

24. NON-UNIFORM CONTAMINATION IN CLEANING

There are two contamination situations to be considered in the cleaning of manufacturing equipment. In one case, contamination from a prior lot may be uniformly dispersed in the subsequent product lot. For example, residue in a mixing tank is uniformly distributed in the next product lot to be manufactured in the same tank. This type of contamination is usually addressed according to the method of Fourman and Mullen. In the second case, contamination from a prior lot is not uniformly distributed in the subsequent product lot. For example, residue in a filling line is distributed primarily to the first few vials to be filled in the next product lot to be manufactured.

Question: How is non-uniform contamination handled in cleaning validation?

25. Problems With Excipients

Pharmaceutical excipients or inactive ingredients may have great influence on various attributes of the final dosage form. Excipient variation is a source of variation in manufacturing processes. Consistency of excipient quality is important for robust manufacturing processes. Identification of input variables and strategies to control variation have been identified by FDA as a necessary requirement for validated processes.

Question: What are problems experienced with pharmaceutical excipients? How are these problems controlled?

26. Packaging Process Validation

The validation of packaging processes is an important process in pharmaceutical manufacturing. Packaging processes may include processes that are critical to the final product such as filling primary package containers with liquid dosage form. The product expiration date is based on the final packaged product. Packaging processes may also include relatively simple processes involving secondary packaging having minimal effect on the product.

Question: What is the preferred approach for packaging processes? Are we validating a packaging process, or are we qualifying packaging equipment?

27. Process Validation Of Granulation-Drying-Sizing Solids Processes

A typical solid product (tablet, capsule, granules, etc.) manufacturing process includes consecutive wet granulation, drying, and particle size reduction unit operations.  Dried granulated solids produced after these unit operations are often the first processed materials to be tested in the process validation of a solids processing process.

Question: What testing is conducted for process validation after the granulation-drying-sizing stage of solids processing?

28. Conformance Lots For Process Validation

The number of product lots to be manufactured for the validation performance phase of validation may vary depending on the situation.  New products without a previous manufacturing history in most cases require the most extensive validation effort.  Other situations may require the same or a lesser number of validation conformance lots.

Question: What are considerations to determine the number of lots required for the validation performance phase of process validation?

29. Understanding the cleaning process

The lifecycle approach to process validation emphasizes greater understanding of processes to be validated by means of laboratory studies and development work conducted in advance of process validation (9, 10, 11). These concepts are similarly applicable to cleaning validation. LeBlanc has discussed the need for cleaning process understanding (12, 13). The Journal of Validation Technology has also presented QbD applications to cleaning and cleaning validation (14, 15). Often, however, cleaning processes are implemented based on historical application or without benefit of scientific and technical development.

Question:What are your experiences in which laboratory studies or development work providing cleaning process understanding significantly influenced or improved the cleaning process or cleaning validation?

30. Process validation strategy for multiple dosage strength products

Most pharmaceutical products are marketed with multiple dosage strengths for patient dosing convenience. Products may have three or four dosage strengths or may have many different dosage strengths; for example, levothyroxine sodium is marketed in 13 different dosage strengths containing 12.5 mcg to 300 mcg active drug/tablet, and warfarin sodium is marketed in 10 different dosage strengths containing 1 mg to 25 mg active drug/tablet. Products may differ in amount of drug content, formulation, color, and other distinguishing characteristics.

Question: What are process validation strategies for multiple dosage strength products?

Paul Pluta, Ph.D., has more than 30 years of pharmaceutical industry experience and is a long-standing adjunct faculty member at the University of Illinois College of Pharmacy in Chicago. Pluta has coordinated the JVT “Benchmarking” column and was a valued member of the JVT Editorial Advisory Board for several years.

Additionally, Pluta was Validation Manager at Abbott Global Pharmaceutical Operations in North Chicago, Illinois, where he was responsible for validation projects and associated activities including manufacturing process validation, cleaning validation, packaging validation, and support systems qualification. Pluta has been involved in nearly all phases of pharmaceutical development and manufacturing, including R&D formulation and process development, dissolution, regulatory, stability, quality assurance, compliance, specifications, technical support, and validation/qualification.  He has more than 30 years of pharmaceutical industry experience. Dr. Pluta’s experience as an adjunct faculty member at the University of Illinois College of Pharmacy in Chicago has included graduate student teaching, undergraduate teaching, and the student externship program. He has presented numerous academic lectures and scientific presentations at pharmaceutical industry meetings. He coordinates both the “Benchmarking’ and “Validation Learning Center” column in the Journal of Validation Technology. He is a member of AAPS, ISPE, and PDA.