Guidance 034 – 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.

The factors listed in the practice standard are typically associated with packaging runs requiring multiple shifts. However, the principle underlying the practice standard remains applicable to all packaging processes, large or small, automated or manual. This principle is the identification of sources of variability that are likely to occur during routine operation.

Manual packaging processes typically require little or no validation since the output of the process is 100% verified by a trained operator performing the task. However, even manual processes should be evaluated for sources of variability that may lead to unacceptable product which might go undetected. If such a condition exists, then the process should be validated.

Semi-manual and fully automated processes require a similar evaluation for sources of variability. The source(s) of variability should be eliminated or reduced as much as possible prior to validation. The validation itself should focus mainly on errors that may go undetected and demonstration that acceptable product is consistently produced.

Examples are provided below for consideration. These examples are only intended to be illustrative of the rationale for determining factors such as lot size for packaging validation: the example should not be applied at the gmp site without conducting a case-by-case assessment of the process to be validated.

Example 1: Manual packaging process

Batch Size: 2000 units

Process: Sterile units in their sealed primary package are hand-labeled (pre-printed with lot number and expiration date) by 4 operators and then placed on a conveyor which takes the labeled units to a packaging station where 4 units are manually placed into a manually assembled, pre-labeled carton by 2 operators. The cartons are conveyed to a second packaging station where they are manually transferred into a shipping container.

Evaluation: All packaging operations are manual, each step of the process can be 100% verified by the operator conducting the process step. The physical handling of the sealed sterile unit is assessed to determine if the operator can inadvertently induce a sterility breach under routine packaging conditions, no such risk is found. Container closure integrity is assured via separate studies. Placement of the labeled unit into a carton does not impact the quality of the product or affect any batch record specific to labeling of the product. The software and system used to generate the labels has been qualified. The pre-labeled cartons meet specification and are approved for use by incoming inspection. Transfer of the cartons into the shipping container does not impact the quality of the product or affect any batch record specific to labeling of the product.

Definition of Validation Lot Size: Validation of the process is not required as continuous monitoring is performed at a low-risk. Instead, release of the product will depend on meeting acceptable AQL (Acceptable Quality Level) levels for defects.

Example 2: Semi-manual packaging process

Batch Size: 200,000 units

Process: 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.

Evaluation: 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.

During this operation, potential sources of variation include shift changes, shift breaks, environmental conditions, and material variability. Material variability mostly affects shrink- wrapping, but this is not a critical to product quality or major defect. Variability of the bottle could affect printing, but a range of material types were qualified during the OQ (Operational Qualification) of the labeler so this has been adequately addressed. The environmental conditions in the packaging area are controlled, but tend to run warmer and more humid during the day and cooler with less humidity at night, this would most likely impact the ink used for the ink jet labeling and therefore the legibility of the lot number and expiration date. Shift changes occur every 8 hour shift and shift breaks occur twice during a shift.

Definition of Validation Lot Size:

In a 24 hour period, 3 shift changes occur and the variation between daytime and night time temperatures can be accounted for in the validation. Therefore, a validation lot could be defined as “one shift = one validation lot” in the packaging validation protocol, and each of the three shifts would be evaluated.

Example 3: Fully automated packaging process

Batch Size: 160,000

Process: One freeze dryer is able to lyophilize an entire batch of a sterile protein product. The lyophilized, sealed and capped vials are held in bulk, pending individual packaging orders for different countries. A typical packaging order is 10,000 units, but may vary dependent on demand. The packaging line can automatically label, carton, shrink-wrap and box 10,000 units in less than 4 hours.

Evaluation: The process validation addresses the lyophilization, sealing and capping steps. Automated equipment and sterilization were also validated separately. The “expected variability” is the variability that would be likely encountered during a “routine” production run. In this example, packaging of an entire order, regardless of the actual batch size, is the most representative of actual operation conditions.

Definition of Validation Lot Size: For the purpose of validation, one packaging order (of representative size) equals one validation lot. However, it should be noted that if packaging order sizes increase to the point where new sources of variability are introduced (such as multiple shifts to package one order) the packaging validation should be re-evaluated. If there are other products to be packaged on this line with larger batch sizes, it may be advantageous to design a bracketing/matrix strategy to include both a small packaging order and a large packaging order.

Example 4: Fully automated packaging process

Batch Size: Various.

Process: A filler utilizes vibration and gravity to move tablets/capsules from a hopper through a series of slats. Cavities in the slats determine tablet/capsule count per bottle. Tablets/capsules are separated and transported by the slats, through a manifold into the bottles. Feed screws, timed to the filler slats, control the flow of bottles into the fill area and hold the bottles in place for filling.

The change parts, 3 sets of slats, can accommodate a large variety of products. The site intends to package 46 different SKUs (Stock Keeper Units or package presentations), encompassing 6 product families and 5 bottle sizes on this filler.

Evaluation: The product families are evaluated and three “worst-case” products are identified based on variabilities such as slat size and dose unit durability. The largest tablet uses the largest slat size and the largest bottle size. The smallest tablet uses the smallest slat size and bottle size and is also the softest and most friable tablet, presenting the biggest challenge to the gravity/vibration feed system. The smallest tablet also represents the largest batch size and therefore takes the longest to fill and so includes a number of shift changes and breaks that may introduce variability to the filling process. Since the filler also fills capsules, a capsule product is selected as it requires a unique blade eject slat. These three products cover all slat types and also bracket the smallest and largest bottle sizes on the line. The impact of bottle dimensions and unit count on the process is recommended to be included in the assessment. The properties and parameters of the three products cover the range of all products filled with this filler, ensuring that reproducibility of the process is covered by the 3 packaging runs.

Definition of Validation Lot Size: One full packaging order of maximum typical size from each of the “worst-case” products is selected and three runs are validated.

Example 5: Semi-automated secondary packaging process

Batch Size: 150,000 units

Process: Two-grams of an OTC (Over the Counter) cream are filled in pre-printed tubes. The filled, pre-printed tubes are then individually packaged into a display carton, the carton is imprinted with lot number and date, and 48 of the cartons are placed in a shipping box for distribution.

Evaluation: The filling of the tubes with the correct fill weight, and crimping with lot number, was validated as part of the process validation. The filled tubes are manually transported to the packaging area and periodically loaded into a hopper for the cartoning process. The cartons are automatically constructed, a tube placed in each, and then folded closed. The cartons are manually stacked in the shipping box. The lot number and expiration date are burned into the carton using a thermal printer. A risk assessment of the process finds no significant sources of variability to the process through equipment functions, environmental conditions, personnel or packaging materials.

Definition of Validation Lot Size: With no identified or presumed sources of variability, it is likely that some portion of the batch will provide sufficient data from which to evaluate the process. It is determined by a technical/risk assessment that approximately 10% of the overall batch size is sufficient to provide an adequate sample pool that is representative of the packaging process. To ensure reproducibility, the validation will include three consecutive batches of at least 10% of the cream batch size.

Example 6:Fully automated secondary packaging process with 100% automated inspection

Batch Size: 250,000 units

Process: A fully automated packaging line receives sterile filled and sealed syringes of parenteral product from a classified area. First, the empty syringe is rolled continuously in front of a light source with a vision detection system to check for particles or glass defects, unacceptable units are automatically rejected. Next, a plunger rod is screwed into the plug (seal) at the back of the syringe. Sensors verify the placement of the plunger and control the amount of pressure applied. A second vision detection system checks the position of the plug seal to verify that the seal was not disturbed during plunger insertion. If the seal is moved beyond a specified limit, it is automatically rejected. Then, individual syringes are placed in the molded compartment of a 6-pack tray. A vision system verifies the presence of all 6 syringes in the tray. Trays missing syringes are rejected. The trays are inserted into a sleeve and the sleeve is labeled with lot number and expiration date. A vision system verifies the presence of the label and the variable data on the label. The sleeves are placed 5 to a carton with an instructional insert. Both the sleeve count and the presence of the insert are automatically verified. The carton is labeled with lot number and expiration date (also verified by vision system) and placed in the shipping box.

Evaluation: Each unit operation and quality control check (vision system/sensors) have been independently qualified and challenged (detection capability, reject functionality, response to start/stop mode) during system validation (IQ/OQ/PQ) activities. The line is continuous, but utilizes accumulators between some unit operations to manage the flow of product. The function of each unit operation is independent of the previous unit operation in that items that do not meet quality requirements are detected, tracked and removed from the line through qualified checks and reject mechanisms. This is performed before the item could affect the ability of the subsequent unit operation to carry out its defined function. A risk assessment of the line indicates no significant source of variability from environmental conditions, personnel or packaging materials and that the only aspect of the packaging process not yet addressed is the efficiency (e.g. throughput, yields) of the packaging operation. The NOR (normal operating range) is narrow relative to the PAR (proven acceptable range) and automated lot monitoring as described above was suggested as sufficient. Production efficiency per se is not a GMP issue and therefore no packaging validation is required. Instead, acceptance of each batch will be dependent solely on routine release parameters and an Annual Product Review may be relied upon to assess any negative trends in packaging.

Definition of Validation Lot Size:

Not applicable.

Example 7: Fully automated packaging process

Batch Size: 250,000 units (Two shifts)

Process: A new product at site. A will be transferred from facility 1 to facility 2. All capsule dosages have a common blend. The difference between dosages is the filling weight. Dosages:

120 mg, 180 mg, 240 mg, 360 mg, and 420 mg. The packaging presentations and capsules sizes are: