Standard/non-standard processes
The non-standard process is determined by a combination of the nature of the active substance, the nature of the finished product, the actual process itself, and the production experience of the manufacturer. All biological products are considered to be non-standard.
The following categories are examples of products or processes which could be considered as nonstandard, and for which production scale validation data should be provided in the marketing authorization application dossier unless otherwise justified:
1. the manufacture of specialized pharmaceutical dose forms;
2. the incorporation of some new technology into a conventional process;
3. (highly) specialized processes involving new technologies or an established process known, or likely, to be complex and therefore to require particular care;
4. non-standard methods of sterilization.
In addition, a manufacturing process type not previously approved for pharmaceutical products within the EU is usually considered a non-standard process.
1. Specialised pharmaceutical dose forms -Standard/non-standard processes
A non-exhaustive list of types of products that might be considered as “specialized” is provided below for illustrative purposes:
• preparations for metered-dose inhalation in the lungs e.g., pressurized metered-dose inhaler (MDI’s) and dry powder inhalers (DPI’s);
• suspensions, emulsions or other liquid dispersed sterile products;
• modified-release preparations;
• unit dose products containing drugs in low content (≤2% of the composition);
• other specialised dose forms e.g., parenteral depot preparations based on biodegradable polymers, liposomal preparations, micellar preparations, nanoparticulate preparations.
2. Conventional pharmaceutical processes incorporating new technologies – Standard/non-standard processes
A conventional process is well established and approved, and could, for example, include such activities as tableting using wet granulation. However, the introduction of new technology into such a conventional process e.g., a new drying technology not commonly used by the pharmaceutical industry, might result in the need for full-scale validation data based on a case-by-case consideration of the product and process development studies.
3. Specialised processes or established processes known to be complex – Standard/non-standard processes
• processes with critical steps such as lyophilization, microencapsulation;
• processes where the physicochemical properties of the active substance or a key excipient (e.g., lubricant, coating agent) may give rise to processing or scale-up difficulties, or stability problems during manufacture at larger scale;
• aseptic processing.
4. Non-standard methods of sterilisation – Standard/non-standard processes
• terminal sterilisation by moist heat using conditions other than pharmacopoeial reference conditions;
• terminal sterilisation by irradiation using less than 25 KGy.
Matrices and Bracketing in Process Validation
Product packaging, such as where only a minor adjustment in packaging parameters is required to accommodate different bottle heights or dosage counts.
Matrixing across different products may be applied to the packaging validation of the final dosage form, for example, to evaluate the packaging of different products in a common packaging presentation. As with other uses of bracketing and matrixing, the risk of using this strategy for the potential products encompassed by the matrixing plan should be considered, documented, and approved.
The use of bracketing/matrixing for the validation of a manufacturing process across different products should be approached with caution because of the risk of overlooking other possible affects of the change. Use of this type of bracketing/matrixing requires a good understanding of the processes involved and the risks being assumed. For example, in the evaluation of a change of a critical material for different products, the excipient interactions, critical process parameters and critical quality attributes (CQAs) are not necessarily the same for each product.
The effect of the change in the CQAs may be different for each product. A product sensitive to the change may experience a failure in a CQA (e.g. dissolution) while in a case of a product not sensitive to the change, it may experience no effect at all in its CQAs.
To obtain the maximum benefit with minimum risk from bracketing and matrices, it is necessary to have a well-developed understanding of the impact of critical process parameters on critical quality attributes. There should be a documented and justified rationale that explains why one set of test conditions (e.g., manufacturing process,
product presentation, etc.) is representative of one or more related test conditions.
Typically, the rationale is addressed by selecting parameters and/or products that represent the edges of a range of
worst case
of allowable conditions.
The rationale and justification for the bracketing/matrixing strategy to be used in validating a process should be provided in the validation protocol, or in another document referenced in the protocol.
Depending on the circumstances, prospective and concurrent validation approaches may be used for validating a process using bracketing or matrixing. If a concurrent approach is used, an interim report provides a summary of the results obtained for a product batch, in order to justify the validation and release of one of the product presentations within the bracket/matrix.
This approach may also assist in approving the manufacturing and/or release of additional batches of a particular presentation. At the completion of the validation, the validation report will address all batches.
At present, some regulatory authorities may not accept the use of bracketing or matrixing for validation. Japan, for example, currently requires that all combinations be validated.
The following examples include possible matrixing/bracketing approaches. There may be other acceptable approaches.
Definitions
At-line:
The measurement where the sample is removed, isolated from, and analyzed in close proximity to the process stream.
Bracketing approach:
A validation scheme/protocol designed such that only batches on the extremes of certain predetermined and justified design factors, e.g., strength, batch size, pack size are tested during process validation. The design assumes that validation of any intermediate levels is represented by the validation of the extremes. Where a range of strengths is to be validated, bracketing could be applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system.
Control strategy:
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to the active substance and finished product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10)
Continuous process verification:
An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8)
Critical process parameter (CPP):
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8).
Critical quality attribute (CQA):
A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (ICH Q8).
Design space:
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters have been demonstrated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8)
Enhanced approach:
A development approach where risk management and scientific knowledge are used to identify and understand the material attributes and process parameters that influence the critical quality attributes of a product.
In-line:
The measurement is where the sample is analyzed within the process stream and not removed from it.
Lifecycle:
All phases in the life of a product from the initial development through marketing until the product’s discontinuation. (ICH Q8)
Ongoing process verification:
Documented evidence that the process remains in a state of control during commercial manufacture.
Online:
The measurement where the sample is diverted from the manufacturing process and may be returned to
the process stream.
Pharmaceutical quality system (PQS):
Management system to direct and control a pharmaceutical company with regard to quality. (ICH Q10)
Process validation:
The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.
Traditional approach:
A product development approach where setpoints and operating ranges for process parameters are
defined to ensure reproducibility.
Delayed Release:
Release of a drug (or drugs) at a time other than immediately following oral administration.
Extended-Release:
Extended-release products are formulated to make the drug available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form).
Immediate Release:
Allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging
the dissolution or absorption of the drug.
Modified Release Dosage Forms:
Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended-release drug products.
Stratified Sampling
The process of selecting units deliberately from various locations within a lot or batch or from various phases or periods of a process to obtain a sample.
Stratified sampling of the blend and dosage units specifically targets locations either in the blender or throughout the compression / filling operation which have a higher risk of producing failing content uniformity results.
Reference: Guideline on process validation for finished products – information and data to be provided in regulatory
submissions
