1.20: Good Manufacturing Practices (GMPs)

Learning Objectives

Goals:

• Make a batch of Good Manufacturing Practice (GMP) popcorn within a specified timeframe (1.5 hours).
• Use Standard Operating Procedures (SOPs) to accomplish the manufacturing task.
• Understand the complexity of the GMP process.
• Understand Quality Control (QC) and Quality Assurance (QA).
• Understand the need for team members to complete individual jobs appropriately to accomplish goals.

Student Learning Outcomes:

Upon completion of this lab, students will be able to:

• Explain the role of Standard Operating Procedures (SOPs) and batch/lot Records.
• Employ the principles of a quality systems approach to manufacturing.
• Learn the difference between Quality Control (QC) and Quality Assurance (QA).
• Discuss the value of teamwork.

Part I: Review Terms and Background Information

Introduction

In everyday speech, quality is a relative attribute like beauty. However, in the Life Sciences or any other manufacturing-related industry quality means compliance to specifications. Quality systems are comprised of the policies, processes, and procedures for maintaining a product with specifications.

This lab exercise will utilize the manufacturing of a popcorn snack as an example where good manufacturing practices (GMPs) can be followed. The exercise used the components of a Quality System. Students are the employees with tasks to accomplish within the defined QA/QC parameters.

Quality Management Systems (QMS)

Quality is the business of the entire company. Generally, companies build their quality systems by first making a commitment by management to design and deliver a ‘quality’ product. The term quality management system refers to the organizational resources, processes, and procedures to implement quality management. In the case of pharmaceuticals, diagnostics and medical devices, these requirements mean the product is EXACTLY what was tested in clinical trials.

Figure 1: Symbiotic relationship between the Quality System, Quality Assurance, and Quality Control

Quality product management is usually implemented through two departments; quality assurance (QA) and quality control (QC). The QA department plans activities and develops the processes that guarantee the accuracy and precision of outputs. QC performs the actual tests during the process and on the final product to ensure that specifications are met. Quality Assurance is process oriented and focuses on defect prevention, while quality control is product oriented and focuses on defect identification. QC refers to a measuring process, or to check a result and provide assurance that all activities are performing within predetermined limits.

Often, QMS systems are explained in this simple statement: “Say what you do, do what you say, document it.”

Say What You Do = SOPs

Standard Operating Procedures (SOPs) and documentation are essential components of a QA program. The management team is responsible for ensuring adherence to the QA plan and SOPs. Essential to this process is documentation of the proposed quality system and processes used by the company.

Perhaps the most important form of documentation is SOPs. SOPs are validated methods that are at the technical core of the product or service. To determine whether methods are fit for their intended purpose, the selected methods must have established accuracy, precision, calibration and limits of detection and quantification. All methods must be fully validated for accuracy and precision before a company starts to sell its product or service.

Do What You Say = Follow the Process (SOPs)

Quality systems are implemented in many sectors of the life sciences industry including manufacturing, a testing laboratory, clinical trials or even Research and Development. In all cases the SOPs must be followed. In the example of a manufactured product, all manufacturing employees follow the defined process and document that they have done so. The QC department provides the process checks and balances. For example, they manage the acceptance and release of raw materials, in–process checks and testing of the final product.

Document It = Evidence of Quality

If you didn’t write it down = you didn’t do it!

No documentation = no PROOF you did it!

No documentation = BAD product and lost money for your company

Current Good Manufacturing Practices (cGMPs)

The general principles that all QMS have in common are:

• Say what you do. Quality, safety, and effectiveness must be designed and built into the product, not tested or inspected into the product.
• Do what you say. Each step in the manufacturing process must be documented and controlled to ensure the finished product meets design and regulatory specifications.
• Document it. Process documentation provides evidence of compliance with cGMPs.

Statistical Process Control

Another aspect of a quality program it use of statistical process control (SPC), which utilizes statistical methods to evaluate variability in procedures. In the design of the product, multiple data sets are obtained to establish accuracy and precision criteria. These criteria are documented in the Master Record. QC testing procedures ensure SPC through instrument calibration and validation, in process testing, final product testing, raw material testing etc. They use process control charts to monitor the process and procedures in order to manage variability.

The purpose of the quality systems is to ensure quality. Since quality is defined as compliance to specifications, a statistical process control (SPC) must be established to ensure this compliance. The SPC requires understanding of both the accuracy and precision required in the product.

Accuracy is the ’right answer’ or ‘bulls-eye". Accuracy is not always known but when it is, it is part of the process. Precision is reproducibility. Whatever the process or procedure, the quality system is there to ensure reproducibility.

The ideal situation is when precision and accuracy are on target: Expected and observed values are close and the results are consistently reproducible. If results are reproducible but the results are not close enough to the expected value, one has good precision but poor accuracy. Poor precision but good accuracy occurs when the results are not close to each other in value but they all fall within an acceptable target range. This situation often can be improved upon with the appropriate action. Poor precision and poor accuracy is typically the most problematic result since neither reproducibility nor an expected target value have been achieved (Figure 2).

Corrective and Preventative Actions (CAPA)

The purpose of the Corrective and Preventative Actions (CAPA) system is to serve as a feedback loop to identify and investigate all quality problems. CAPA policies are central to a quality system. Part of the QC testing that takes place on every lot of product, is to assure compliance to specifications. If the specifications are not met, it is important to determine what is the root cause of the problem. Until the root cause is used to identify the cause of problems with accuracy and precision, product quality cannot be assured.

Figure 2. Accuracy and precision

Quality Assurance and Quality Control (QA/QC)

Table 1. Quality Assurance Versus Quality Control

Element	Quality Assurance (QA)	Quality Control (QC)
Definition	the activities focused on the processes for preventing mistakes and producing products free of defects	a set of activities concerned with monitoring and verifying resulting products meet the defined standards and specifications for quality
Purpose	Verification: Answer the question "Am I building the product correctly"? Prove the system meets all specified requirements at a particular stage.	Validation: Answer the question "Am I building the right product"? Ensure that the product meets customer expectation.
Type of process	Proactive	Reactive
Goal	Plan to prevent problems	Identify defects in the finished product Identify and correct source of product defects
Tools	Statistical Process Controls: Control Charts Run Charts	Statistical Quality Controls: Random Acceptance Sampling Range Charts Histograms Means Standard Deviation
Responsibility	Everyone	Quality Control Group

Part II: Train and Prepare for a Production Run

A. Lab Activity: Review the Lab Flow

Construct a flow diagram of the following overview of the training and production of your component for the snack product today.

Scenario: Your company, Awesome Snacks Company (ASC), needs you to produce popcorn for their seasonally available Summer Snack Mix. Your job will be to take the raw material and produce the popcorn that goes to the Snack Mixing Department.

Materials needed:

microwave popcorn bags, microwave, digital balance, forms ASC001-004

1. Employee Overview

• Supervisor (teacher) – Welcomes Employees (students) to Awesome Snack Company.
• Overview of QMS and why it’s important to the company.

2. Group Formation

• Divide employees up into Quality Assurance Teams (5 employees each team)

3. Training

1. Supervisor gives training form (see figure below, in QA packet) and packets to team.

Figure 3. Heading of training document in packet

2. Team Assigns Jobs to Members
   1. Material Control Tech.
   2. Quality Control Tech.
   3. Manufacturing Tech. I
   4. Manufacturing Tech II
   5. Quality Assurance Tech.
3. QA Tech Reads SOP Standards 11-001 to team
4. QA Tech distributes packets to each team member
   • Members read through their training packet
5. Team completes ASC Training Document
6. The completed ASC Training Document must be turned in to the supervisor (instructor) to receive material to start the production run.

4. Production

1. Each technician performs their role
2. Document everything on company forms
3. Put the following calculation from ASC Form 004 into your laboratory notebook:
   • Percent weight loss for each of the three bags.
4. Evaluate: Does batch meet specification?
   • Statistical Process Control: Mean, Standard Deviation, and Coefficient of Variation
5. Post Production Product Specifications: Release or Reject
   • Are you accepting or rejecting this batch? Why?
6. Once everything is completed, QA will turn forms into Supervisor

5. Corrective Action Plan

1. Class discussion of Statistical Process Control
2. Corrective and Preventative Action plan is constructed.

B. Activity: Training Using Good Manufacturing Practices (GMP)

PURPOSE: Every employee must be trained in conformance with GMP (Good Manufacturing Practices).

MATERIALS

• 1 official SOP Standards for Employee Safety and Conduct: STANDARDS 11 -001 (see below)
• 1 official Awesome Snack Company (ASC) Documentation of Training Document (see below)
• 1 Set of the Standard Operating Procedures (SOPs) for Production: MAT-11-001, MAN-11-001, MAN-11-002, MAN-11-003, QA-11-001, QC-11-001
• 1 set of production forms: ASC 001, ASC 002, ASC 003, ASC 004

PROCEDURE

Form Groups, Assign Roles, Complete Training

1. The ideal group size is 5. Form groups and assign roles (jobs) to each member of Production Team. Jobs: Quality Assurance (QA), Quality Control (QC), Manufacturing Tech I, Manufacturing Tech II, Material Control (MC). Note: If the team is comprised of a group less than 5, 1 member must take multiple roles.
2. Follow the training instructions below. After training, the documentation of training document (Figure 4) must be turned in to the supervisor (instructor) to receive material to start your production run.

Figure 4. The heading of SOP 11-001 from your packet

Instructions:

1. Quality Assurance (QA) Technician will read SOP Standards-11-001 to the Team.
2. QA Technician distributes signs, SOPs and ASC Forms to each team member.
3. Each team member reviews the scope and ASC guidelines, signs the page and receives a supervisor (or their designee) signature (see below)
4. Each team member reads the SOP for his/her job to identify their primary activity. (Ex. Weigh unpopped popcorn (UPP))
5. QA fills out table 2 below. In the order presented, QA lists the activity and asks the name of who will do it.

SCOPE

• ALL ASC employees must be trained, acknowledge training, and receive sign-off from a supervisor.
• Not following the stated ASC guidelines may result in written warning and/or termination of employment

The ASC Guidelines include but are not limited to the following:

1. All hair that is shoulder length or longer must be tied back or contained in a hair net
2. Fingernails must be neatly trimmed. Fingernails should not protrude past the ends of the fingertips more than ¼ inch
3. Clothing and other personal belongings must be stored in designated areas
4. All jewelry is prohibited in all manufacturing areas with the exception of one smooth ring (no stones) on finger. This includes and is not limited to watches, multiple rings, ear, nose, tongue, eye, belly piercings or rings...etc. are not allowed
5. No items are allowed in pockets or affixed to clothing above the waist in the manufacturing area. The exception is for PPE (Personal Protective Equipment)
6. Electronic devices such as cell phone, iPods, blue tooth, radio, pager, MP3, handheld games, etc. These items may be stored in lockers. Employees may use these devices only in designated areas during breaks, lunch, before and/or after work
7. Areas must be left in a clean and organized manner at the end of each shift
8. No food (including gum, candy, nuts and/or similar snacks) and/or drinks can be stored or consumed in manufacturing areas
9. Every glass or plastic breakage in any manufacturing area must be reported to the Shift Supervisor or Safety Coordinator and a Quality Incident Report generated
10. Use the following format for dates: Day-Month-Year (ex. 05-Mar-2019)
11. When Initialing, use THREE initials, to include your middle initial

I, ___________________________ , certify that I have read and understand the ASC Guidelines.

Employee Full Name

Employee Signature		Supervisor Signature
Date		Date

Table 2. Assignment of Production Roles

ACTIVITY	WHO DOES THIS JOB? (NAME)	SOP/FORM
Inspect and/or Release, Reject UPP*		MAT-11-001 / ASC 002
Start Lot/Batch Record		QA-11-001 / ASC 001
Prepare and clean microwave/ balance		MAN-11-001, MAN-11-002, / ASC 003
Inspect Cleaning; OK production start		QC-11-001 / ASC 003
Weigh UPP		MAN-11-003 / ASC 004
Produce IPP*		MAN-11-003 / ASC 004
Place popcorn in Reject or Release		MAT-11-001 / ASC 002
Complete Lot/Batch Record		QA-11-001 / ASC 001
If necessary, initiate CAPA

*UPP= unpopped popcorn; IPP= in process popcorn

12. Print name and Initial on the OFFICIAL Documentation of Training document (looks like below) after training on Standards and SOPs is complete. Be sure to include your middle initial
13. Once completed, Material Control turns in the document in to Supervisor (Instructor) to receive the starting material (UPP) and start production

Table 3. Documentation of Training

JOB TITLE	NAME (Print)	INITIALS (Include Middle Initial)
Material Control Tech
Quality Control Tech
Manufacturing Tech I
Manufacturing Tech II
Quality Assurance Tech

This is similar to the official document to be used and completed during the exercise.

Part III: Production and Documentation

Perform Roles and Document Appropriately Using Company Forms

Procedure

1. • 1. Use official company SOP documents to perform the assigned roles in Table 1.
     2. Document appropriately on the “official” Awesome Snack Company (ASC) forms as listed in Table 1

Results

ASC form 004 (IPP production report) is to be completed by your team and turned in to your supervisor (instructor) along with ASC forms 001, 002, 003.

Put the following calculations from this form into your laboratory notebook:

1. Percent weight loss for each of the three bags. Are you accepting or rejecting this batch? Why?
2. Statistical Process Control:
   • Mean:
   • Standard Deviation:
   • Coefficient of Variation:
3. Post Production Product Specifications: Release or Reject

Study Questions

1. Did you need to implement CAPA? Explain the deviance that caused this procedural process to begin and explain the corrective and preventative process you implemented. This will be shared with the class during discussion.
2. The Ishigawa fishbone diagram (Figure 4) is a tool used to determine the root cause of a problem. It enables a team to brainstorm and categorize all the potential problems that could be the cause of a problem so they can be systematically eliminated until the real cause or causes is/are identified.
3. With your team come up with all the potential reasons your popcorn may fail to meet quality specifications because it is burnt. Redraw the diagram, including the title, and fill it out in your laboratory notebook.

Figure 4. Blank Ishigawa fishbone diagram.

Attribution:

Adapted from Lab 20 Good Manufacturing Practices by Sandra Slivka, PhD, Southern California Biotech Center, San Diego Miramar College, CA. Licensed CC-BY-NC-SA 4.0