Pharmaceutical Validation Documentation

The FDA's May 1987 definition of validation,contained in the General Principles of Validation, is still considered the gospel of computer control systems. According to this guideline validation involves "establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes."
The FDA demands that biotech and pharmaceutical manufacturers prove that processes will consistently do what they are proposed to do. This includes the proper operation of computer hardware and software. Although the FDA doesn't define the type or format of documentation required to validate each system, certain formats are accepted and expected.
A Validation Plan, sometimes called a Master Plan, is a clear and concise explanation of management philosophies and expectations concerning the validation programs. Specifically, it will outline responsibilities for each phase of the system design and the implementation process.
Protocols are written records clearly defining the objectives and methods that will be used for the validation programs. An important part of the protocol is the description of the testing method including who will test the system, how they will test it and what data is to be collected and reported.
Computerized system protocols often include the three distinct stages as described in PMA reports: Installation Qualification (IQ), Operational Qualification (OQ),and Performance Qualification (PQ).
Protocol Changes are documented requirements specifying who and how changes to parameters, thresholds, and acceptance criteria are made after approval. It is not impossible tomake changes after or during testing, but these changes must be properly implemented and approved to be validatable.
Specifications are written to clearly and completely describe what a system will do. These are rather lengthy descriptions of every hardware component (valve, motor, thermocouple, etc.— there can be thousands), how it communicates with the controller, and what each step in the automated sequence will accomplish. It will include all measurable and meaningful operating parameters. This document is reviewed and approved by responsible personnel at the manufacturer's facility before implementation.
The Factory Acceptance Test requires a document describing specific inputs that must be activated with the resultant outputs they produce for every step of the automated sequence. This document allows for management sign off or confirmation that each part of the entire control system has been tested.

Validation protocol and report

Process Validation
A suggested scheme for the validation protocol and subsequent report concerning a particular process is shown below:
Part 1. Purpose (the validation) and prerequisites
Part 2. Presentation of the entire process and subprocesses, flow diagram, critical steps/risks
Part 3. Validation protocol, approval
Part 4. Installation qualification, drawings
Part 5. Qualification protocol/report

5.1 Subprocess 1

5.1.1 Purpose
5.1.2 Methods/procedures, list of manufacturing methods, SOPs, and written procedures, as applicable
5.1.3 Sampling and testing procedures, acceptance criteria (detailed description of, or reference to, established procedures, as described in pharmacopoeias)
5.1.4 Reporting

5.1.4.1 Calibration of test equipment used in the production process
5.1.4.2 Test data (raw data)
5.1.4.3 Results (summary)

5.1.5 Approval and requalification procedure

5.2 Subprocess 2 (same as for Subprocess 1)
5.n Subprocess n

Part 6. Product characteristics, test data from validation batches
Part 7. Evaluation, including comparison with the acceptance criteria and recommendations (including frequency of revalidation/requalification)
Part 8. Certification (approval)
Part 9. If applicable, preparation of an abbreviated version of the validation report for external use, for example by the regulatory authority
The validation protocol and report may also include copies of the product stability report or a summary of it, validation documentation on cleaning, and analytical methods.

process validation Approaches

3. Approaches

Two basic approaches to the validation of the process itself exist (apart from the qualification of equipment used in production, the calibration of control and measurement instruments, the evaluation of environmental factors, etc.), namely the experimental approach and the approach based on the analysis of historical data.
The experimental approach, which is applicable to both prospective and concurrent validation, may involve:

• Extensive product testing.
• Simulation process trials.
• Challenge/worst case trials.
• Controls of process parameters (mostly physical).

One of the most practical forms of process validation, mainly for non-sterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications, and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then treated statistically to verify the "normality" of the distribution, and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications.
Similarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Products (intermediate or final) may occasionally be tested for non-routine characteristics. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets/capsules tested for dissolution profile if such tests are not performed on every batch.
Simulation process trials are used mainly to validate the aseptic filling of parenteral products that cannot be terminally sterilized. This involves filling ampoules with culture media under normal conditions, followed by incubation and control of microbial growth. In the past, a level of contamination of less than 0.3% was considered to be acceptable; however, the current target level should not exceed 0.1%.
Challenge experiments are performed to determine the robustness of the process, i.e. its capacity to operate smoothly when parameters approach acceptable limits. The use of ranges of parameters for the quality of the starting materials in experimental batches may make it possible to estimate the extent to which the process is still capable of producing an end-product that meets the specifications.
The physical parameters of the process are monitored in normal production runs to obtain additional information on the process and its reliability. Extra temperature-sensitive devices installed in an autoclave or dry-heat sterilizer (in addition to probes used routinely) will permit an in-depth study of the heat distribution for several loads. Heat-penetration measurements are recommended for injectable products of higher viscosity or with volumes larger than 5 ml. A tableting press equipped with pressure-sensitive cells will be helpful in collecting statistical data on the uniformity of die-fill and therefore on mass uniformity.
In the approach based on the analysis of historical data, no experiments are performed in retrospective validation, but instead all available historical data concerning a number of batches are combined and jointly analysed. If production is proceeding smoothly during the period preceding validation, the data from in-process inspection and final testing of the product are combined and treated statistically. The results, including the outcome of process capability studies, trend analysis, etc., will indicate whether the process is under control or not.
Quality control charts may be used for retrospective validation. A total of 10-25 batches or more are used for this purpose, preferably processed over a period of no longer than 12 months, and reviewed together. (Batches rejected during routine quality control are not included in this review since they belong to a different "population", but failure investigations are performed separately.) A critical quality parameter of the end-product is selected, e.g. the assay value or potency, unit dose uniformity, disintegration time, or extent of dissolution. The analytical results for this parameter for the batches under review are extracted from past batch release documentation and pooled together, while the results from each batch are treated as subgroups. The grand average ("process average") and control limits are calculated and plotted on graphs or charts in accordance with the instructions given in numerous publications on control charts (see Bibliography, page 91).
A careful review of the charts will enable the reliability of the process to be estimated. A process may be considered reliable if the plotted data are within the control limits and the variability of individual results is stable or tends to decrease. Otherwise, an investigation and possibly an improvement are needed.¹

¹ It may be noted that, once control charts for past batches have been prepared, they become a powerful tool for prospective quality management. Data for new batches are plotted on the same charts and, for every result outside control limits, a reason, that is a new factor affecting the process, is sought and, when found, eliminated. By consistently applying this approach over a period of time the process may be considerably improved.

In addition, information on product-related problems is also analysed. The reliability of the process is demonstrated if, for a considerable time, there are no rejections, complaints, returns, unaccountable adverse reactions, etc. The process may be certified as retrospectively validated if the results of statistical analysis are positive and the absence of serious problems is documented. However, it should be emphasized that this approach is not applicable to the manufacture of sterile products.
Table 1
Example of priorities for a process validation programme

Type of process	Validation requirements
New	Every new process must be validated before approval for routine production
Existing: Processes designed to render a product sterile	All processes affecting sterility and manufacturing environment must be validated; the most important is the sterilization stage
Non-sterile production	Low-dose tablets and capsules containing highly active substances: validation of mixing and granulation in relation to content uniformity
	Other tablets and capsules: validation of tablet compressing and capsule filling in relation to uniformity of mass

Types of process validation

1. Types of process validation
.Depending on when it is performed in relation to production, validation can be prospective, concurrent, retrospective or revalidation (repeated validation).
Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps: these are then evaluated on the basis of past experience to determine whether they might lead to critical situations.
Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set. The trials are then performed and evaluated, and an overall assessment is made. If, at the end, the results are acceptable, the process is satisfactory. Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory. This form of validation is essential in order to limit the risk of errors occurring on the production scale, e.g. in the preparation of injectable products.
Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. The first three production-scale batches must be monitored as comprehensively as possible.¹The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.

¹ This careful monitoring of the first three production batches is sometimes regarded as prospective validation.

Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product.
Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated. Recorded difficulties and failures in production are analysed to determine the limits of process parameters. A trend analysis may be conducted to determine the extent to which the process parameters are within the permissible range.
Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule. For tablets which have been compressed under individual pressure-sensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. On the other hand, it should not be applied in the manufacture of sterile products.
Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.
Revalidation may be divided into two broad categories:

• Revalidation after any change having a bearing on product quality.
• Periodic revalidation carried out at scheduled intervals.

Revalidation after changes. Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent.
Revalidation after changes may be based on the performance of the same tests and activities as those used during the original validation, including tests on subprocesses and on the equipment concerned. Some typical changes which require revalidation include the following:

• Changes in the starting material(s). Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product.
• Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability.
• Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality.
• Changes in equipment, including measuring instruments, may affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process.
• Changes in the production area and support system, e.g. the rearrangement of manufacturing areas and/or support systems, may result in changes in the process. The repair and maintenance of support systems, such as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the manufacture of sterile products.
• Unexpected changes and deviations may be observed during self-inspection or audit, or during the continuous trend analysis of process data.

Periodic revalidation. It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made.
The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during in-process and finished product testing after the latest validation, aimed at verifying that the process is under control. During the review of such historical data, any trend in the data collected should be evaluated.
In some processes, such as sterilization, additional process testing is required to complement the historical data. The degree of testing required will be apparent from the original validation.
Additionally, the following points should be checked at the time of a scheduled revalidation:

• Have any changes in master formula and methods, batch size, etc., occurred? If so, has their impact on the product been assessed?
• Have calibrations been made in accordance with the established programme and time schedule?
• Has preventive maintenance been performed in accordance with the programme and time schedule?
• Have the standard operating procedures (SOPs) been properly updated?
• Have the SOPs been implemented?
• Have the cleaning and hygiene programmes been carried out?
• Have any changes been made in the analytical control methods?

2. Prerequisites for process validation

Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e. before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc.
Other aspects of manufacture must be validated, including critical services (water, air, nitrogen, power supply, etc.), and supporting operations, such as equipment cleaning and sanitation of premises. Proper training and motivation of personnel are prerequisites to successful validation.

Validation of PLC software. (automation in the pharmaceutical industry)

InfoTrac OneFile (R)

Control and Instrumentation , 05/01/1995 v27 n5

Validation of PLC software. (automation in the pharmaceutical industry) Wootton, Paul *~|~*

COPYRIGHT 1995 Centaur Publishing Ltd.

How do you go about validating a PLC system in the pharmaceutical industry? When a pharmaceutical manufacturer realises that validation of either an existing or new computer system is required, and enters into a contract with a supplier, it's important that a working relationship is established. This has to be more than a mere purchase order supply agreement, and has to account for the needs and responsibilities of both parties.
Validation is the documented evidence that a process or system does what it's supposed to do. In the pharmaceutical industry, this means that a process must manufacture the final product within established limits and specifications and that each step of the process be recorded. A computer system which controls the process must operate in a manner that will maintain these product specifications.
This is often thought to extend from the generation of the functional design specification (FDS) through to what is often called a site acceptance test (SAT) of hardware and software (provided by the supplier, based on the functions in the FDS). The requirements to withstand a regulatory body (FDA/MCA) inspection do, however, go much deeper than this.
For pre-qualification, the specification and design criteria for the system must include: a description of the purpose of the system; a list of the functional requirements; normal operating parameters; operational limits; back-up procedures; report formats; security provision; MMI; hardware; PSU specs; and operational environment.
The system description must refer to the final version to be installed (new systems) or to that which is currently being used (existing). All the hardware and peripherals should be listed, together with their equipment numbers and, for software, the data storage requirements and back-up procedures defined. The applicable version of the operating system and application programs must be stated by name and programming language. A schematic of the system should also be included.
An installation qualification verities that hardware, and its installation, meet the specification and design. It should include: hardware installation; power supply; integrity of communications; environmental conditions; security; maintenance; and installation drawings.
Get the evidence
Meanwhile, the operational qualification provides evidence that the system performs as designed. It includes: test equipment; standard operating procedures (SOPs); product application; software identification; software functions; and SOP verification and compliance. There's also: start-up, shut-down and menu selection test; interlocks; testing the computer with normal and abnormal demands and worst-case conditions (at the data handling limits); environmental conditions; and back-up procedures.
The system should be subjected to a series of tests designed to confirm that it will reliably and reproducibly carry out the tasks for which it was designed. These should include: software control routines; data integrity; system capacity (that it's able to operate under worst-case situations); and power failure (effects and action).
Any audit by regulatory bodies, for example the FDA, would begin with a systems overview, a look at environmental factors (physical location, EMC, shielding) before moving on to the major areas of validation. This is where records and documentation are critical to achieve a successful audit.
Many companies use third party consultants for validation. This need not be necessary if a user chooses a systems provider that understands the concepts of validation and has a quality plan (evidenced by ISO9001).
RELATED ARTICLE:
* Silvertech uses two checklists:
* Computer hardware/software validation requirements, based on information from Validation of automated systems in pharmaceutical manufacture, from the PICSVF/ISPE
* A validation programme, taken from the Guide to inspection of computerised systems in drug processing, from the US Food and Drug Administration.
Paul Wootton is with Silvertech.

InfoTrac OneFile (R)