Journal of Validation Technology Volume 8 Number 2 January 2002 Institute of Validation Tecnology
Process Validation of Synthetic Chemical Processes for the Production of Active Pharmaceutical Ingredients (APIs)
By Roger W. Koops, Ph.D.
Genelabs Technologies, Inc.

A key component to successful process validation of synthetic chemical processes for the manufacture of Active Pharmaceutical Ingredients (APIs) is developing a comprehensive validation program. This paper describes an approach to establishing such a program starting with a corporate policy through the various components of the validation exercise. A lifecycle approach to the validation concept is critical, and begins with the development program and does not end until the product is retired. Circumstances that are unique to synthetic chemical pathways are presented. The paper describes specific details and examples for establishing validation master plans, validation protocols, and writing the final validation report. Additionally, other topics such as deviations and failures, homogeneity, shipping, and process trending are discussed.

The paper describes activities that relate directly to manufacturing and quality assurance components of such a program. However, the paper does not attempt to deal with a corresponding program in analytical methods since this is a subject of its own. Additionally, the paper does not deal with any detailed aspects of equipment cleaning validation for the same reason as described above for analytical methods. Equipment cleaning methods should be developed in situ with chemical process development, and cleaning validation should occur either prior to or concurrent with process validation.


Active Pharmaceutical Ingredient (API): A substance intended for use as an active ingredient in a finished dosage form of a drug. Such a substance is intended to furnish pharmacological activity in either the diagnosis, cure mitigation, treatment, or prevention of a disease.1

Intermediate: A compound that is produced en route to an API. The compound has all or at least a portion of its structure that is incorporated into the structure of the final API.

Development Report: A report, or series of reports, that describe in detail the development history of an API or intermediate. The report should include a summary of all laboratory experiments used to support the current process, and include a comprehensive batch history profile with a summary of all process changes.

Policy: A written ideology or philosophy concerning a certain subject, and the basis for which procedures are established.

Procedure: A written set of instructions on how to perform a specific task, e.g., Standard Operating Procedures (SOPs).

Quality Assurance (QA): An independent unit that reviews documentation and activities for compliance to Current Good Manufacturing Practice (cGMP).

Quality Control (QC): An independent unit that performs laboratory testing on a compound using prescribed methods. Included in this definition are groups that are responsible for developing and validating test methods, performing routine release testing, and maintaining stability programs.

Critical Parameter: A processing parameter that has a critical effect on the downstream processing or quality profile of the intended product. If the parameter is not tightly controlled, the downstream process and/or quality profile of the product could be negatively impacted.


Process validation is arguably the most important event that occurs during a product’s process lifetime. Too many companies view process validation as a tedious event that takes time, money, effort, and is only needed to satisfy the FDA. Although born as a result of regulatory considerations, process validation should be viewed as a scientific event. That is, process validation is a demonstration and verification of the science that went into developing a process, and should be viewed as a significant accomplishment in the science and art of process development.

What is process development? It is the documented demonstration that all of the effort that went into developing a process has led to a process that will consistently produce a given product. This means that process validation does not begin with the first batch to be validated, or the protocol, or the master plan. Rather, it begins in the laboratory at the earliest stages of process development, and is a continuous event that follows a process throughout its lifetime. When viewed in this fashion, and developed in a proactive, comprehensive manner, one has established a program that supports the quality and success of the product. This paper will describe an approach on how to develop this type of program.

Does this mean that, if performed correctly, such a program will guarantee problem-free processing for the life of the product? Certainly not. Humans may like to believe that they can master nature, but nature shows us all too often that we are mistaken. Simple or complex chemical processes all have the ability to go their own path, albeit, many times with the helping hand of humans. This paper will also describe approaches to dealing with problems that may be encountered during process validation.

The Validation Program

A successful validation program is comprised of many components, many of which need to be implemented well in advance of the actual validation exercise itself. Using a sports analogy, the success of the performance (i.e., validation execution) depends upon the effort and efficiency that went into preparing for the event (i.e., preparation and training). Therefore, a successful validation program begins at the very early stages of process development itself, and does not culminate with the validation event, but rather when the process eventually retires. It is a process lifetime event.
A validation program is comprised of many components including the written aspects (policies, procedures, protocols, etc.), the personnel (departments, technical experts, consultants, etc.), and activities (qualification, training, etc.). All of these components should be described and coordinated into a functional, comprehensive program.

Figure 1 depicts a typical hierarchical approach to such a program through a program pyramid. The view can be expressed that the top levels of the hierarchy govern the program, but the foundation to success is in the science that is put into process development, equipment and facility qualifications, analytical method development, etc. and ultimately in personnel expertise and training.

Corporate Validation Policies

A comprehensive corporate validation program is assembled beginning at the very top with a well-defined validation policy. The policy should outline the organization’s general validation expectations over the lifetime of the process. The policy should define the scientific expectations and documentation that begins from the first day of process development. Some examples of these expectations are described in Figure 2.
An important aspect of such a global policy is that it exposes employees, who may have very special tasks, to the broader validation program. The employees then become better trained and cognizant of their role in the validation program. For example, chemists who may be normally focused on process development will do much better in organizing their data, writing reports, etc. if they understand what purpose their data and conclusions will serve in the end when process validation protocols are assembled and executed. General training in the concepts of process validation should be given to all individuals who are part of the development and manufacturing program.

Another important feature of the policy should be the participation of development personnel in the actual validation exercise. Development personnel are generally the most knowledgeable concerning the process, and can ensure that the technology has been appropriately transferred into the commercial manufacturing environment. In addition, the experience of participation is invaluable to the chemist and will help them during the development phase.

Finally, the policy should describe the responsibility of maintaining the product/process during the product lifetime (lifecycle approach). Each organization may have a different infrastructure that is used to accomplish this. The policy should describe the responsibility for monitoring and trending, process improvements, change control, etc.

Corporate Procedures Related to Process Evaluation

In today’s world, it can be said with a high degree of certainty that most API processes are multi-step synthetic pathways that generally may involve at least one complex chemical transformation. A reasonably accepted validation axiom is that the final process step that produces an API (and any purification thereof) needs to be validated. However, a debate can be started as to when to perform process validation when intermediates are involved. Therefore, an approach to an evaluation procedure for intermediates will be suggested.

There is no simple answer to the question of when to apply process validation for intermediate steps in a multi-step process. Each process must be independently evaluated. However, this does not mean that a coherent policy or procedure cannot be established that describes how that evaluation process should take place. In fact, putting such a procedure in place only benefits those that are trying to conduct the evaluation. How should the question of when to validate intermediate process steps be approached in a procedure?

Even though each process needs to be evaluated independently, there are some common factors and criteria that can be applied when conducting an evaluation. Multi-step synthetic processes can be classified at the simplest level as either being linear or convergent, or a combination of both approaches. In a linear synthesis, a starting material is either built upon, re-arranged, or further elaborated through chemical processes to eventually achieve the desired molecular structure. A convergent synthesis, on the other hand, builds pieces of the molecular structure independently, and then assembles the pieces to achieve the desired molecular structure. Many processes incorporate both elements.

The first step of the evaluation is to determine what the starting material is, what are isolated and non-isolated intermediates, what is (or are) the ultimate intermediate (or final intermediate), and what synthetic scheme will be required to produce a final API. In fact, determining what constitutes a starting material is a debatable issue.

This author has generally taken the following approach in evaluating whether a material is a starting material. First, the material should be a readily available item that has a standard grade (or grades) associated with it, and has been well characterized. It may be produced under contract by a vendor, but in that case, it should be produced by a known and established process, and the end product should be, again, capable of achieving a standard grade. Second, the vendor should be qualified (under a vendor qualification program) so to ensure that a material meets consistent quality standards. A rudimentary quality agreement should be established to outline change notification and quality requirements.

If a material is manufactured by a contract party and the process was supplied by the innovator, the material is simply a third-party manufactured intermediate. The contractor now becomes an extension of the innovator, and the transferred process must be included in the full validation evaluation.

Once a starting material has been established, each intermediate needs to be evaluated in two ways:

  1. How it contributes to the final API, particularly in regard to the impurity profile, and
  2. The specific process for that intermediate. Although isolated intermediates should be fully evaluated, non-isolated intermediates should also be evaluated, since there may be processes where stricter controls may be required.

For example, an intermediate may not be isolated due to structural instability when not in solution. In this case, concentration and/or potency of the intermediate may be a critical attribute that needs to be controlled.

During development stages, an emerging impurity profile of the API should emerge. This profile should be split into two separate profiles to include the final purified API and the initial crude API. From the crude API, an impurity fingerprint can be established concerning the process. Questions can be asked such as what intermediate process steps may contribute to the crude profile? What are the boundaries for purification to the final API? What should be the desired quality attribute of intermediate A in order to achieve the desired end product? This is why it is important to characterize process impurities as early in the development process as possible.

From this type of evaluation, each intermediate process step can be evaluated as to its relative importance in the end product. If an intermediate needs to be controlled since it could contribute to an adverse quality profile of the API, process validation should be applied.

Another reason to employ process validation is if an intermediate step is particularly difficult to control or is technically difficult. Process validation in these cases would help ensure that the manufacture of the intermediate is consistent and is performed with an appropriate level of attention.

An important factor in approaching any process validation evaluation is to avoid considering it only a regulatory requirement to which only a minimal effort should be applied to satisfy the regulatory requirement. Rather, process validation should be viewed as a scientific approach to ensure critical processes have the integrity required to make a quality product. Additionally, process validation makes good business sense in that well-developed and validated processes ultimately save time and money and increase quality, which is accomplished by reducing, although rarely eliminating, costly batch failures, investigations, inappropriate or inefficient processing, constant reprocessing, etc.

Finally, there has always been some discussion whether the validation exercise should be designed so as to “stress” the accepted parameters by operating at the maximum or minimum accepted level, or to aim for the target of each parameter. Some companies have attempted to matrix the parameter limits in an effort to test the extreme limits of process parameters. Which approach is used may depend on the individual process.

However, as a general rule, this author has held the view that the development phase is the place to clearly establish the boundaries of the operating ranges, and how each extreme between parameters affects the final outcome of the process. Process validation, by definition, is used to demonstrate consistency and, thus, should target the desired operating parameter. From a manufacturing standpoint, it is advantageous to operate based upon the targeted parameter values for batch consistency.

The Process Development Report

The Process Development Report (PDR) is the starting point for any process validation activity. The PDR should compile reports and data on the process starting from the first laboratory preparation and continuing through pilot scale on to commercial production. Ideally, interim reports should be prepared during the development process, that will make the compilation of the PDR easier to manage.

The PDR should be able to tell the story of how a process evolved from the first laboratory scale synthesis to the applicable scaled up version. The PDR should also provide data and references that supports the current process, identify the critical process parameters and how to control them, and describe the expected impurity profile. The PDR should describe the characterization of the major impurities that compose the impurity profile, and the development efforts to minimize or eliminate impurities.

Although the PDR is a technical document, the data contained therein supports the validation activity. The PDR should be used as a basis for developing the validation parameters for the product in question. The PDR should summarize the data in a level of detail that is sufficient to describe the development cycle for the process. Any reader should be able to get a thorough understanding of the process history by reading the report.
Development reports can be (and frequently are) requested during a regulatory inspection. Although QA may not be required to approve a development report since it is a technical report (although it is highly recommended), QA should audit the development report for complete traceability to the raw data. This is particularly recommended for data that either supports a process step as critical or not. Ideally, this is done prior to approving process validation protocols.

The PDR is a living document and should be continuously updated through the product lifecycle. Many firms create a PDR and then ignore it once process validation starts or is completed. Since improvements to a process can be made throughout the lifetime of the process, these improvements may require additional validation work and regulatory filings. These changes and improvements should initiate an update of the PDR. At a minimum, such documentation practices reflect good scientific discipline.

The Process Validation Master Plan

The process Validation Master Plan (VMP) is the blueprint to all of the process validation activities. The VMP should describe the entire synthetic route to the API, identify which process steps require process validation, identify starting and raw materials and the sources of these materials. If process validation will be performed at any contact manufacturer that is used to provide an intermediate or API, the VMP should describe the relative responsibilities for each organization.

Figure 3 lists some of the components that should be included in a VMP. The VMP should not be too detailed as the validation protocol itself is really the document that should provide all of the details. The VMP is also a living document, and should be amended or updated as needed if the plan changes, with the appropriately documented change justification. However, good thought and planning should be put into the original VMP since too many changes to a VMP may give an impression of a poorly planned validation or weak validation program.
The VMP should be readily available to all personnel who will be critical players in the validation exercise, including contract sites, as applicable.

The Process Validation Protocol

The process validation protocol will describe, in detail, the “how to” for the validation exercise. Any procedure should be either described in detail in the protocol or a reference should be provided to an already established procedure for handling the task. The protocol should be used in training all individuals who will be involved in process validation.

There are many components to the protocol and the more critical components are described in Figure 4. All components of the validation should be described in the protocol. These would include equipment and facility qualification documents, materials and specifications, sampling procedures, analytical testing (both in-process and final), analytical methods, etc.

The protocol should be drafted to be as concise and instructive as possible. Where applicable, data should be entered directly into the protocol. If an exercise is particularly complex, a series of protocols may be preferable. Protocols should have places for reviewers’ initials or signatures.

Essentially, the protocol resembles a master record in many ways, but it does provide a greater level of descriptive detail regarding the execution of the process, monitoring of the critical steps, sampling instructions, etc. It is not necessary to repeat all of the instructions that are in the master record, however, critical steps and operations that are unique to the exercise should be fully described.

Critical Parameters

The identification of critical process parameters is the key to a successful process validation exercise, and to maintaining process consistency throughout the process lifetime. The processing parameters need to be evaluated carefully throughout the development process to truly determine the critical parameters (this is where a well-written PDR is most useful). Figure 5 provides some examples of parameters that may be determined to be critical in a chemical process. A critical parameter can represent a chemical reaction issue, an engineering issue, or a combination of both.

In some cases, process parameters may need to be classified in different categories than either critical or non-critical. API manufacturing can be very complex, and a parameter may be considered critical, but not necessarily lethal to the process. One challenge to any process validation program is to clearly define the various types of critical parameters. The following is an example of how this might be approached:

Process Critical Parameter: A process parameter that if not maintained within established limits would lead to a process failure. This would require routine in-process testing to ensure maintenance of the parameter. For example, a reaction is run at 50 ±2ј C, but the product will rapidly decompose starting at 58ј C. This temperature is critical, and if not maintained, could lead to a failure.

Process Value Parameter: A process parameter that if not maintained within the established limits could impact the normal course of the process (but may not lead to a failure). This type of parameter may require strict monitoring and verification, but may not require routine in-process testing to control the outcome. For example, an ionic aqueous solution is required for extraction of an organic phase. If the ionic strength is insufficient, an emulsion can form, leading to longer settling times or indeterminate phase separation. In this case, the length of the process could be affected without having impact on the overall batch.

The key to defining critical parameters is in understanding all aspects of a given process, and ensuring that the right level of control is given to the parameters that need it. One common mistake that is made is defining critical parameters only in terms of the chemical process; engineering parameters frequently are overlooked. It is important to reinforce the concept that a chemical process is the intertwining of both chemical and engineering aspects.

Some organizations chose to define parameters only if they could affect the impurity profile or the ability of a material to pass specification. However, the ability of a material to meet specification is not the sole indicator that the process is running smoothly or that it is validated. Critical parameters can also affect things such as yield, without affecting the material specifications. Therefore, the validation protocol should establish criteria for yields, and should be consistent with normal process yield experience during development. Abnormal yields, such as too high or too low, should be a red flag that there may be a problem. A high yield, for example, could mean an unexpected contamination with some salts, incomplete or non-uniform drying, or some other serious problem that could impact the quality of the final product.

Finally, the degree to which a critical parameter can be monitored is dependent on the choice and sensitivity of the analytical method. Therefore, it is important to reiterate that the analytical method development and validation program has equal importance towards the success of process validation.

Equipment and Facility Qualification

In general, it is best to have all facility and equipment qualifications completed prior to process validation (certainly all IQ/OQ should be completed). Performance Qualification (PQ) can be performed during process validation, but it is generally advisable to have completed this testing prior to process validation since it would add additional risk to the exercise. However, there may be some instances where it is useful to concurrently perform an equipment or facility PQ during process validation. In those cases, a separate PQ protocol should be drafted and referenced in the process validation protocol.

The Process Validation Report

The process validation report should summarize the results of the process validation exercise. If a multi-step synthesis is being validated, each process step that has a validation protocol associated with it should have a final report for that step. A final governing validation report should be written that summarizes the entire effort. A report should be written even if a problem was encountered during the execution of the validation and it was unsuccessful. In this case, the report should describe the investigation conclusion, and the anticipated course of action in correcting the problem.

The validation report is also a scientific document, and as such, should be concise and technically clear. The results of the validation exercise should be summarized (all raw data should be referenced for complete traceability), preferably in tabular form with the acceptance criteria (as stated in the protocols) tabulated as well. The acceptability of the results versus the pre-defined acceptance criteria should be indicated by either a passing or failing notation. In cases where a criterion failed, a discussion should be given concerning the failure, and include the cause of the failure, the affect of the failure on the validation, corrective actions, etc. All deviations should be listed, and a brief summary of each given along with an impact assessment. A definitive statement should be made as to whether all of the criteria have been met and the process is considered validated. Failure to provide a definitive conclusion is an error that is seen commonly in validation reports. Figure 6 outlines some sections and content of a validation summary report.

The report should also identify the process parameters and components that, if changed, would require additional validation (i.e., revalidation). Reference should be made to the current change control procedures that will govern those changes.

Process Validation Deviations and Failures

Clearly, it is foolhardy to begin process validation without an assurance that the process is under control, and this is related to the process development program in general. However, even the most well developed process will encounter a deviation or problem. How this problem is handled can make the difference between a successful process validation or validation failure. One common theme when reviewing FDA Warning Letters concerning process validation is what companies do (or don’t do) when validation problems are encountered, even if the problem is major and the answer is clear (e.g., recognizing a validation failure). In many of these cases, it becomes clear that the process was not ready for validation to begin with, and a price is now being exacted for rushing or cutting corners. One common cause of these failures is due to not properly identifying the critical process parameters.

Most scientists will agree that it is more cost effective to spend time up-front to properly develop a process, rather than attempting to fix it after problems are encountered. Nevertheless, many companies insist on doing the opposite by attempting to validate a process that is not fully developed or in control. Of course, there are constant budgetary pressures that apply to any development program. However, with proper planning and a good, proactive program, it will provide a better tool to project the appropriate budgetary needs, and develop a good process that will pay for itself in the end by being prepared for validation.

Major problems are generally obvious in the outcome. Batch failures that cannot be attributed to operator error or equipment breakdown unrelated to maintenance issues are considered validation failures.1,2 What about problems that are less clear? The key is a thorough and well-documented investigation. In the end, a decision must be made regarding the impact of the deviation or problem on the validation exercise. This is also where a clear set of pre-defined scenarios (in the protocol or VMP) can make the path very clear. For example, if a failure is encountered due to (blank), then do (blank). The advantage of pre-defined scenarios has already been discussed, but this also includes management approval that there are occurrences and conditions which everyone agrees in advance will require a fresh start.

The approach to an investigation is the same for any deviation, and goes back to a fundamental approach to scientific inquiry. The following steps should be performed as soon as possible after the problem is discovered:

  • Document clearly what occurred and when it occurred.
  • Interview personnel as soon as possible (before memories can get clouded) and document the interview.
  • Collect any additional data (as is relevant).
  • Describe a sequence of events of when and what happened, review batch records, and corroborate events through data and records.
  • Document any and all remedial actions that may have been taken.
  • List all possible causes for the event.
  • After investigating, eliminate causes that do not fit the data.
  • Establish a cause or most probable cause based upon the data.
  • List corrective actions that need to be implemented.

Both from a regulatory perspective and a scientific perspective, any problem that was related to the process means that the validation was impacted. If the problem was serious enough to cause a failure, the validation was not successful. Only events that are not process-related could be written off as not negatively affecting the validation (e.g., power failures, natural disasters, human error, etc.). Even if a process validation failed and the cause was not process-related, the validation should be replaced with a fresh run.1 Ideally, an interim summary report can close the event, and the VMP should then be amended to include the additional process validation run(s). In all cases, the QA unit is required to approve the documented investigation, conclusions, remedial and corrective actions, assessments of impact, etc.

Process Validation, Third-Party Manufacturing, and the Virtual Company

In a contract situation, all process validation responsibilities should be fully described in a quality agreement between the two parties. The contractee, who is typically the owner of the Investigational New Drug (IND), New Drug Application (NDA), or Abbreviated New Drug Application (ANDA), is ultimately responsible for the product supplied from the contractor. This means that you must be a part of reviewing and approving validation documents (protocols, reports, and data). Since the contractee is ultimately responsible for the work of the contractor, the virtual company should prepare a comprehensive validation master plan, even though the validation work will be performed by a contract organization. The VMP should fully describe the roles and responsibilities of each organization in addition to the items previously discussed.

Establishing clear-cut policies and expectations is of particular importance when dealing with contract organizations. European firms typically have a different view on validation and qualification than in the U.S. Thus, the concepts of process validation may not be as universally interpreted as your organization’s definition. Therefore, it is important to define these expectations early on in the relationship (preferably during the evaluation phase) so that no surprises are discovered when it counts. These expectations are best defined in a good quality agreement.4

For contractors, it is important to recognize the value in providing a detailed quality agreement or a written set of expectations from your customer (not all virtual companies may be experienced enough to bring this to the table). It is incumbent on either side to take the lead in these situations and be preemptive to avoid any potential misunderstanding. Once there is a problem, especially during or after process validation, there will be a tremendous effort required from both organizations to correct the situation.

Finally, it is important that the virtual company have a person-in-the-plant policy, especially during process validation. Although you have hired another company to manufacture (perhaps even develop the process) for you, you must share in the knowledge and expertise of the process.

Special Topics


The homogeneous nature of the final API is a very critical characteristic that must be demonstrated, and this should be done during process validation. Ideally, homogeneity should be demonstrated at that stage of the process where it is expected to be achieved, not necessarily as a final packaged product. The process step where homogeneity testing is frequently employed is the drying step. Typically, three types of dryers are used:

  1. Tray dryers
  2. Tumble dryers
  3. Filter dryers

In each case, the validation protocol should include a sampling plan and frequency to test various locations and times of the drying process. These data should demonstrate the product uniformity during the drying process. Sampling and testing may also be desirable on the filtered wet cake prior to any drying activity to demonstrate homogeneity of crystallization or filtration. Testing at this stage can be focused on attributes that are applicable such as assay, impurity profile, Organic Volatile Impurities (OVI), loss on drying, moisture, etc.

Finally, the packaged product should undergo a comprehensive homogeneity sampling and testing regimen. This should include a combination of physical (appearance, particle size, powder flow, etc.) and chemical tests (assay, impurities, heavy metals, OVI, etc.). A sampling plan should be developed that provides a good matrix for demonstrating homogeneity. The plan should take into consideration the size and volume of the final packaged product. If a material is easily compressed, a compression study should be included, and may be included with a shipping study (see section below).

Shipping Studies

The final packaged API should be subjected to shipping studies. Stability programs are designed to show the stability of a material under storage, but they do not test movement of the product during shipment. A shipping study can be performed at any time once the final packaging and shipping characteristics are identified. However, it is often convenient to include it in the validation exercise. A shipping study should incorporate the use of portable temperature and humidity monitors to show the environmental conditions that the material has been subjected to during the normal course of shipping. Stress tests of the packaging materials may be performed, but should probably be performed on a suitable placebo. Stress testing should address the conditions of shipment that could impact the quality of the material being shipped (e.g., temperature, humidity, permeability of primary and secondary containers, etc.).

APIs that have stringent storage requirements (e.g., refrigeration or frozen), should have equally strict acceptance criteria for the shipping study. If a special shipping container is required, or if a consumable coolant (e.g., dry ice) is utilized, the protocol should include all procedures for preparing the shipment, training of personnel, etc.

Stability Testing

API: Each process validation batch should be placed in a stability program. Ideally, stability data has already been accumulated to establish a retest period for the API. The stability protocol can be either a standard protocol, or drafted with the validation protocol specifically for the validation exercise, and should include normal and accelerated storage conditions per the International Conference on Harmonization (ICH) guidelines.3

Intermediates: If an intermediate is going to be stored or stockpiled, stability data and retest periods need to be established. Normally, it is a good idea to perform a hold study on intermediates (e.g., one month, two month etc.) in the event of delays in manufacturing, campaigning, etc. The hold study does not necessarily need to be a part of process validation, but should be performed prior to process validation and under a specific protocol.

Monitoring and Trending

The key to maintaining a process is through monitoring and trending the process. An extensive database should be established that collects process data. Typically, the critical quality attributes and the critical process parameters are monitored; however, a particular process may require additional factors to be monitored.

In establishing a starting point for a process monitoring program, a meaningful data baseline needs to be established, and should be from a process that has the parameters of the process well defined. Although it is always beneficial to monitor process parameters during development, a baseline will probably not be initially established until the first validation batches are produced. However, if there were demonstration batches or other batches produced prior to process validation that are equivalent to the validation batches, these could represent a starting point. There may be processes where even early development batches have enough definition to begin this evaluation. However, enough batches need to be produced to provide a sound statistical base for data evaluation. This number probably should be evaluated on a case-by-case basis, and be based on the process and process attributes that are being monitored (since the confidence level is dependent on the number of batches).

An Annual Product Review (APR) is a quality requirement, but in fact, this review should be performed routinely by the appropriate technical group. Process trends should be investigated and addressed, as necessary. This activity should also be captured in PDR updates if there is additional process improvement work that is performed. There are several good software packages available that will assist with routine monitoring and data handling.


Successful process validation programs begin with a thoughtful and comprehensive corporate policy concerning the process validation program. This policy should recognize that process validation begins at the initial stages of development, and does not end until the lifetime of the product is over. It is important that all employees be fully trained and understand their role in the program. Good science, well-documented development programs, proactive procedures and definitions, and well-written protocols will increase the chances of successful process validation.

Finally, process validation does not end at the successful completion of the exercise or final report. Process validation is a lifetime event that requires continuous process monitoring, trending, and evaluation.

About the Author

Roger W. Koops, Ph.D., is currently the Associate Director of Quality at Genelabs Technologies, Inc. and directs the Quality Assurance and Quality Control groups. He has over 11 years of experience in API process development, manufacturing, and quality related areas including process validation, compliance evaluation of API manufacturing, equipment and facilities, third-party manufacturing, and quality systems. Dr. Koops received his Ph.D. degree in Chemistry from the University of California, Riverside, and his undergraduate degree from Western Washington University. He can be reached by phone at 650-562-1441, by fax at 650-368-3198, or by e-mail at


  1. FDA. Guidance For Industry (draft): Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients. 1998.
  2. ICH Q7A (draft): Good Manufacturing Guide for Active Pharmaceutical Ingredients. 1998.
  3. ICH Q1A(R): Stability Testing for New Drug Substances and Drug Products. 1994, (R): 2000.
  4. Bobrowicz, G., The Quality Agreement: Compliance Considerations in Selecting a Contract Manufacturer. BioPharm. Feb., 2001. p 14.

Article Acronym Listing

ANDA: Abbreviated New Drug Application
API: Active Pharmaceutical Ingredient
APR: Annual Product Review
cGMP: Current Good Manufacturing Practice
ICH: International Conference on Harmonization
IND: Investigational New Drug
IQ: Installation Qualification
NDA: New Drug Application
OQ: Operational Qualification
OVI: Organic Volatile Impurities
PDR: Process Development Report
PFD: Process Flow Diagram
PQ: Performance Qualification
QA: Quality Assurance
QC: Quality Control
SOP: Standard Operating Procedure
VMP: Validation Master Plan