2017 MiniBioman Drug Product Manufacturing Day 2 Manual

2017 Mini-Bioman Drug Product Manufacturing Day 2. Manual Inspection of Drug Vials Ivy Tech Community College Bloomington Sengyong Lee, Ph. D Professor and Chair of Biotechnology

• Product SISPQ § Pharmaceutical manufacturing employees are expected to know, understand, and comply with the secondary drug manufacturing requirements that protect “product SISPQ” S: Safety I: Identity S: Strength P: Purity Q: Quality

1. Inspection • Parenteral products must be visually inspected for defined attributes. Every single drug container must be examined for container defects and product defects. • Defects are classified as critical, major and minor defects. • Critical Defect – Life threatening when used as directed. Would trigger product recall § Cracks, bad seals, missing stoppers, microbial contamination, glass delamination § Acceptable Quality Limit (AQL) – 0 • Major Defect A – Nonlife threatening, Would trigger a product complaint § Visible foreign particulate matter § AQL – 0. 25% • Major Defect B – Could trigger product complaint § Discoloration § AQL – 0. 65% • Minor Defect – Could lower customer perception of quality if noticed § Scratches, crooked seals § AQL – 2. 5%

• Each of the defect categories is assigned a numerical value that represents the Acceptable Quality Limit (AQL) : maximum number of each level of defect that can be found during QA inspection without impacting overall batch quality. The American National Standards Institute/American Society for Quality Control (ANSI/ASQC) Z 1. 42008, Sampling Procedures and Tables for Inspection by Attributes is the primary reference used for setting AQL levels. Sample AQL Table based on ANSI/ASQC, Z 1. 4 -2008 501 -1, 200 1, 201 -3, 200 3, 201 -10, 000 10, 001 -35, 000 35, 001 -150, 000 QA Inspection Review Sample Size 200 200 315 800 Allowable Critical Defects 0. 065% 0 0 1 Allowable Major Defects 1. 0% 5 5 5 7 14 Allowable Minor Defects 2. 5% 10 10 10 14 21 150, 001 -500, 000 800 1 14 21 500, 001 and over 1250 2 21 21 Batch Size

The inspection during the secondary drug manufacturing 1. Product filled in primary packaging (vials and syringes) 2. Inspection on counts and gross defects like broken vials 3. Secondary inspection, full inspection in light booths: AQL performed by QA 4. Secondary device assembly (safety devices, auto injectors, other devices/ equipment required by the end user) 5. Secondary packaging and Labeling: syringes or vials are placed in the specific packaging designed for the end user, labeling controls are in place, required labeling is applied and confirmed 6. QA reviews all of the paperwork related to the production of the batch lot and either release it or reject it. 7. If released, additional packaging, labels and product information on storage condition are added. 8. Products shipped to the client who distributes to patients

Manual inspection under a lighted booth

A. Manual Inspection - an inspector physically picks up and examines the drug product containers. The manual inspection process employs the use of a lighted booth with a back wall composed of non-glare material that is divided into two halves, one black and one white. The inspector picks up one or more containers, depending on the size, and examines the container(s) in the lighted booth, once in front of the black background and once in front of the white background. Various defects will sometimes be more apparent when viewed against one color or the other. • The amount of time each container or set of containers is looked at should be limited and defined within the inspection Standard Operating Procedure (SOP). Prolonged examination does not result in a better inspection; it generally results in a high level of false rejects. • Any containers having identified defects are rejected. Each defect is recorded in the appropriate category (critical, major, or minor). • Inspectors must be properly trained and periodically recertififed. • Due to focus and concentration requirements, the maximum amount of time limit for inspection and mandatory break are mandated.

• At the end of the inspection, the number of rejects is totaled. Limits for each defect type or overall defect limits vary to each manufacturer. Some have in-process limits that may trigger a tighter AQL (a larger sample set will be taken for the AQL inspection). Others have limits for percentage of defects that may trigger an investigation if exceeded. There should be a mechanism in place to recognize and react to out-of-trend results that may impact product quality. Basic procedure for manual inspection for identifying particles: • Container of parenteral solution must be free of labels and thoroughly cleaned. • Use dampened nonlinting cloth or sponge to remove external particles. • Hold container by its top and carefully swirl contents by rotating the wrist to move the contents of the container. Avoid creating bubbles through vigorous swirling. • Hold container horizontally about 4 in. below the light source against a while and black background. Light should be away from the eyes of the inspector and hands should be kept under the light source to prevent glare. • If no particles are seen, invert the container slowly and observe for heavy particle that may not have been suspended by swirling. • Observation should last for 5 seconds each for black and white background. • Reject any container having visible particles at any time during the inspection process.

Inspection review procedure • The inspection reviewer reviews both sets of “Good” and “Defects” sorted by inspector. • The reviewer examines the appropriate number of randomly selected vials to fulfill the AQL inspection statistical criteria (ISO 2859). • If the recorded defect is incorrect and should be recategorized, the reviewer makes a correction on the sticker by lining out the defect code and entering the correct defect code. • If the vial does not contain any defects, record it on the passing vial entry on the inspection form. After removing the defect sticker, vial is placed in the “good” set of products. • If the reviewer encounters a vial containing a defect from a “good” set, the vial is labeled with a sticker with an appropriate defect code and recategorized. • If necessary, the reviewer recommend management the inspector to be retrained on a particular defect inspection or to be disqualified as an inspector. • The reviewer completes the product inspection form.

Defect classification • Critical defects – nonconformities that can result in personal injury or potential hazard to end user. The integrity of the container and/or product SISPQ are compromised.

• Major defects – have the potential to impact the integrity of the container and/or product SISPQ. Particulate matters inside the container or in stopper

• Major defects Nonconformities leading to serious impairment of the container or potential impact to product SISPQ.

• Minor defects – cosmetic issues that do not impact the integrity of the container or the SISPQ of the product. Cosmetic defects on outside of the vial, scratch, or glass defect.

b. Semi-automated Inspection - it is a manual inspection with an integrated conveyor and timing system. There are generally several booths linked together and the vials are delivered to the inspectors by the conveyor. The vials travel down the conveyor and stop for the set inspection time. The inspector picks up the vials, performs the inspection in the lighted booth, and places them back on the conveyer to proceed to traying off. This can increase efficiency as the inspectors do not have to handle a single tray at a time and the amount of time spent inspecting each container/set of containers is more tightly controlled. Another advantage is that these systems generally include automated counting so that the inspectors do not have to count the units inspected at the end of the process.

Pharmaceutical Semi-Automatic Inspection Booth courtesy of Dabrico, Inc.

c. Automated Inspection - Fully automated inspection systems involve multiple camera systems for inspecting large numbers of product containers at a high rate of speed. These systems are far more expensive and require extensive testing and validation before they can be used in manufacturing processes; however they are more efficient and effective, especially in the case of larger batch sizes that are tens to hundreds of thousands of units. Automated Vial Inspection Machine Automated Syringe Inspection Using Optical Sensor to Detect Particulates

Manual Inspection Training • An inspector is qualified using a test set that is representative of the product to be inspected. For example, if the product to be inspected is lyophilized, qualify the inspector using the lyophilized test set. • Inspectors are qualified if their detection of rejects is ≥ 70% detection of known rejects and ≤ 30% of blanks (false reject) in any given test set. The inspector must meet this requirement three (3) times before being considered a qualified manual visual inspector. • Two sets of 60 seeded vials in each set are available for your inspection training. Each batch has a certain number of various defects and none defects. Your goal to is identify as many defects as possible to be qualified as an inspector.

• Develop a team with inspectors and reviewers. • The inspectors perform an 100% inspection on a batch (60 vials) following the SOP. • The reviewers evaluate and qualify the inspectors by reviewing the categorized defects and non-defects using the inspection training batch make-up guideline. • The product inspection form should be filled out during the training. The instructor will review your inspection form for your inspection qualification. The accurate identification of the numbers and identities of the defects are critical for the training.