Inspection Attributes in Packaging Validation of Non-Sterile Drug Products

Guidance Summary 031 - 040

Guidance 031 Summary - Inspection Attributes in Packaging Validation of Non-Sterile Drug Products

This procedure provides examples and guidance on classification of defects for packaged non-sterile drug products.

General criteria for inspection and control of defects are described in Appendix 1. Three classifications: critical, major, and minor are used to classify packaging defects. The Tables below on defects and attributes can be used as a starting point for those new to defect classification during packaging validation.

Sample size of multiple plans is less than double sampling plans, which in turn is less than the single sample plans. Once determined, the total sample size is divided by the number of sampling intervals to determine the number of samples per interval (e.g. 200 bottles (sample size) /24 intervals = 9 bottles/interval).

Each application is suggested to be evaluated on a case-by-case basis to determine which defects are critical, major and minor, for that specific package or product line. Depending on the specific package and dosage form, some of the attributes or defects listed below may not be applicable, additional defects may be warranted, or the description of the defect further specified. Definitions of defects may vary from site to site, so the classification is highly dependent on the interpretation and specific definition of the defect. The concepts of AQL (Acceptable Quality Level) and UQL (Unacceptable Quality Level) may be non-uniformly applied in setting acceptance or statistical quality control criterion.

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Guidance 032 Summary - Laboratory Equipment Qualification

The System Owner should ensure that the equipment vendor follows a quality system approach. This can be accomplished by one of the following:

  • Site approved vendor;
  • Previous industry and/or experience with the vendor and/or system;
  • Vendor assessment -vendor assessment may include documentation provided by the vendor or specific request for information that may include vendor surveys; or
  • Vendor audits.

 

Equipment Qualification Documents should include the following equipment information, at a minimum:

  • Description, and
  • Unique Identifications.

 

Qualification documentation package for equipment should include the following information, at a minimum:

  • Required documents as specified in Appendix 1 based on the equipment classification;
  • Intended end-use of the equipment, and
  • Equipment classification.

 

For Moderate and Complex Equipment that Stores Data Electronically, procedures and processes should be in place to ensure data integrity and security.

For complex equipment, aspects of system security, configuration, and electronic data and electronic signatures should be addressed in a local Site procedure or equipment specific protocol or plan.

Supplemental qualification tests should be performed for complex equipment with personal computers connected to the server to verify proper configuration of the system and to verify establishment of the proper user permissions.

Guidance 033 Summary - Matrices and Bracketing in Process Validation

Bracketing and matrixing allow a ‘most appropriate challenge’ condition to be defined for a process or drug product family (the same drug product with different dosage strengths). This risk-based approach can allow the validation to be focused on the most challenging circumstances, or “worst cases.” Use of this approach can provide a significant benefit to reduce the overall validation effort. Bracketing or matrixing may be used for validation of Drug Product, Active Pharmaceutical Ingredient and Packaging processes when this approach can be justified.

Matrixing is typically used when there are significant similarities between products in a drug product family (e.g., same product different strengths in the manufacturing stage or different products with similar container closure in the packaging stage).

Examples of variables that might be assessed by bracketing and matrixing include, but are not limited, to:

  • Batch size;
  • DP dosage strength;
  • Identical equipment (e.g. where setup and operating conditions are the same);

 

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.

A new product will be transferred from one manufacturing site to another. The product is a capsule dosage form. A common blend is used to prepare five different dosage strengths. The packaging presentations and capsule sizes are shown in Table 2:

This example is one of matrixing of the different strengths and capsule sizes. We have solid dosage units with similar capsule size packaged with the same tools in the same type of container/closure (for those that use the same components). It is also an example of bracketing of packaging components for those dosages that have similar components (bottle/closure).

Guidance 034 Summary - Considerations for Selecting Packaging Lot Sizes During Packaging

One of the industry standards in packaging validation indicates that: “A packaging validation lot must be representative of the typical packaging process and be of sufficient length such that packaging validation lot will exhibit normal packaging process variability”. In addition, a packaging validation run (e.g. entire lot or defined portion of a lot) shall be determined by the Validation Committee based on a technical evaluation and experience with the packaging process. For the purposes of validation it should be allowed a lot size to be determined that may not correspond to the full packaging order lot size.

A non-sterile, oral liquid dosage form is filled in pre-labeled plastic bottles, sealed with a tamper-evident seal and capped. The sealed bottle is directly printed with lot number and expiration date using an ink jet printer. The bottles are then placed manually in individual cartons; the cartons are then printed with the same lot number and expiration date. Groups of 6 cartons are shrink-wrapped together. The shrink-wrapped cartons are manually placed in a shipping container. It requires 9 shifts to fill and package all 200,000 units in the batch.

The filling, sealing and capping of the non-sterile liquid should be validated within the scope of the process validation. Subsequent to capping, the packaging process equipment includes a labeler, cartoner, another labeler and shrink-wrapper. The labeling equipment provides batch-record-specific information. Ensuring proper alignment on the bottle/carton is important for legibility.

The potential effect of heat from the shrink-wrapper on the product and packaging materials has already been assessed. The cartoner and shrink-wrapper have no direct impact on product quality. Proper timing of the inter-connected packaging equipment is important not only to the efficiency of the line, but also to prevent damaged bottles, cartons and labeling errors. Transfer of the shrink-wrapped cartons into the shipping container does not impact the quality of the product or affect any batch record specific labeling of the product.

Guidance 035 Summary - Non-Sterile Active Pharmaceutical Ingredient Manufacturing Area

For each API product, a risk-based assessment of environmental control requirements should be performed, documented, and approved by the Site Quality and Production Teams.

The risk assessment may be conducted on a product or facility-centric basis. This risk assessment should include consideration of at least the following:

  • Type of API manufactured (e.g., small molecule API via chemical synthesis or classical fermentation);
  • For APIs produced by chemical synthesis or classical fermentation, the risk assessment should be conducted to include the step where the API molecule is formed and on each of the subsequent step(s) of manufacture, including an evaluation on whether or not there is further purification of the API;

 

Final API steps include where the API molecule is formed and any subsequent manufacturing steps where there is no further purification of the API. The environmental control strategy for these areas should include consideration of the following:

  • Design of the applicable API areas to meet the criteria for the drug product manufacturing area where the API is first exposed in drug product manufacturing [e.g., design of these API areas to meet the comparable ISO 14644 Non-Viable Particulate levels];
  • Temperature and humidity requirements, where specified for the product;
  • Potential for microbial contamination from the environment, if critical to product quality;
  • Pressure Differentials between adjacent areas to avoid contamination of the API product;

Guidance 036 Summary - Potential Critical Packaging Process Parameters and Validation Practices

Quality risk assessments are suggested to be used for determining the level of criticality of equipment and parameters. See guidance on Risk Assessment in Validation. Each packaging application should be evaluated on a case-by-case basis to determine impact assessments and which parameters are critical. Critical packaging and labelling process parameters and normal operating ranges, including justification or reference for these ranges, are to be determined before validation and included in the packaging validation protocol. Some examples of critical process parameters ranges to be determined in pre-studies, line trials or qualifications may include:

  • Time
  • Temperature
  • Pressure
  • Torque
  • Speed
  • Count quantity
  • Fill Weight and Variation
  • Inert atmosphere (liquid)
  • Environmental Humidity

 

A solid dosage form is compounded in various strengths affecting its overall shape and size. Solid dosage units are packaged with the same tools in the same type of container/closure. One validation run for each tablet strength should be included in the validation matrix.

Bracketing of the packaging processes can be performed when there is a range of process extremes of parameters. Different products may be bracketed due to similarities of package components, critical packaging process parameters, packaging lines, and product attributes.

Number of Validation Runs (or segments)

A packaging validation run should be representative of the typical packaging process and be of sufficient length such that the packaging validation run will exhibit normal packaging process variability such as equipment variability, operator and mechanic variability, material variability, start-ups, shut downs, shift changes, and environmental conditions. Some sites use a minimum run time such as 10 hours to capture any potential effects of a shift change

Guidance 037 Summary - Process Validation Sampling for Non-Sterile Liquid Semi Solid Drug Products

This guidance provides Process Validation Sampling guidelines for non-sterile liquid (solutions and suspensions) and semi-solid (ointments, creams, pastes, gels and lotions) drug product dosage forms.

Sampling of solutions pose few special concerns as all materials are in solution and each sample is the same as every other sample if homogenous.

For solutions the key aspects that should be addressed during validation include assurance that the drug substance and preservatives are dissolved and that the solution has been adequately mixed.

 Ointments, Creams, Pastes, Gels and Lotions are often prone to separation or settling and may pose special concerns for sampling.

In formulations where the active pharmaceutical ingredient (API) is soluble in the base or vehicle, API uniformity would be expected to present less of a problem than those formulations where the API is insoluble and is suspended, as may be the case with certain semi-solid dosage forms. In the latter case, API uniformity would depend upon control of particle size, and the use of a validated mixing process.

A concern is mixer design and the presence of “dead spots” where quantities of the formula are stationary and not subject to mixing. Sampling points should include these points as part of the sampling plan.

Guidance 038 Summary - Process Validation Sampling for Non-Sterile Solid Dose Drug Products

This guidance provides Process Validation Sampling guidelines for non-sterile solid dose drug product dosage forms.

There are many concerns regarding blend uniformity sampling, for example:

  • Inappropriate sample thief technology;
  • Powder segregation of samples may occur after sampling;
  • Difficulty in proving that the blender sample plan will be representative of worst-case locations;
  • Segregation of blend that can occur during discharge, storage, and transport prior to final processing.

 

Solid dosage forms typically provide many opportunities for applying appropriate and scientifically sound sampling approaches.

A approach to demonstrating blend uniformity by combining blend testing with in-process dosage unit compendial testing. This approach postulates that the analysis of finished tablets/capsules can support or provide statistical evidence that a failing blend result was due to poor sampling or handling technique.

Guidance 040 Summary - Periodic Review of Processes and Systems

Validated processes and qualified systems (from this point forward refers to equipment & computer systems) are required to be periodically evaluated to verify that they remain in a validated state. High risk processes (e.g. sterile or aseptic) may also require routine re-qualification and/or revalidation. The application of a risk-based approach allows:

–           The prioritization of PR and routine re-qualification/revalidations activities.

–           The scientific justification of the PR frequency and routine re-qualification /revalidation frequency (if applicable)

Routine revalidation is only required for high risk processes (e.g. sterile/aseptic). The types of processes that are typically involved in routine revalidation include sterilization and aseptic processing (e.g. autoclaves, de-pyrogenation tunnels, steam-in-place systems, aseptic filling lines).

If Routine revalidation is required, it is typically conducted using a concurrent validation approach. The testing is executed on a preset frequency against a standardized pre-approved protocol or SOP.

Refer to Appendix 1, step 1, “Identification of system criticality” for guidance on when PR applies or does not apply according to the qualification approach used.

Unless a re-qualification is required for a specific system, where no significant changes have been made to the direct impact /indirect impact systems (that require qualification) /critical system, a PR (with evidence that the system is consistently performing and is fit for use) fulfills the need for re-qualification.

Where applicable, a review of system security, including appropriateness of user access and addition/removal of users is often carried out as a routine activity. If this is the case, then security would not need to be included in the PR. However, if there is no separate management system in place for these activities then they must be included in the PR. For example:

  • Security access and privilege review;
  • Security log review; System log review;
  • System Backup review;
  • Data integrity review, including archived and old data
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