Why is GMP Training a Necessity at Excipient Sites?

Training in Good Manufacturing Practices (GMPs) is a requirement for pharmaceutical manufacturers per 21CFR211.25(a), Personnel Qualifications. All site personnel are expected to attend training, including GMP, as it relates to their functions. Section 3.12 of the ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, also requires employee training in GMPs appropriate to their responsibility. Finally, the Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients requires appropriate GMP training of site personnel as well. It is worthwhile noting that an ANSI standard for Excipient GMP, which is under development, is expected to also establish a requirement for ongoing GMP training. While it is clear that GMP training is required for both drug manufacturers and ingredient suppliers, the extent and frequency of such training differs depending upon the sites’ participation in the pharmaceutical industry.

When developing a site GMP training program for excipient personnel, the site should establish a clear objective for conducting employee training in Good Manufacturing Practices. A statement might read “The objective of GMP training is to motivate our employees through education in the applicable principles of Good Manufacturing Practices to encourage them to perform their tasks in accordance with established procedures and GMP expectations, always with the patient in mind.”

The purpose of training in GMPs should be to ensure hourly employees perform their tasks as instructed and to motivate those employees to notify their supervisor:

  • If they deviate from instructions,
  • Observe a problem with equipment,
  • Notice any material whose appearance is unusual, etc.

GMP training also establishes requirements for the completion of records that confirm instructions were followed and helps assure all relevant documentation is retained. Since the extent and complexity of GMP activities increase from the excipient supplier to the Active Pharmaceutical Ingredient (API) producer, finally to the pharmaceutical drug product manufacturer, the intensity and frequency of training activities increase as well.

The underlying reason for GMP training is to ensure that the site and processes operate in a state of control. The excipient produced has a more consistent composition batch to batch, which assures reproducible performance of the excipient in the pharmaceutical application.

An additional benefit of GMP training is to remind the personnel that the site has procedures and directions that govern site operations. These documents assure that the operations are conducted consistently from person to person and in conformance with management directions.

Finally training sessions should be interactive. Training should provide an opportunity for dialogue between the employees directly involved in production, testing, storage, and shipment of the excipients and the instructor. The proper environment encourages the attendees to discuss their concerns and question required practices. Attendees can use the training session to alert management of improvement needs and opportunities.

All employees at a pharmaceutical manufacturing facility, with direct or indirect involvement in any activity related to the production of drug products, receive ongoing training in GMP appropriate to their function. This includes the plant or site manager down to line operators. Similarly a large proportion of employees at API manufacturers are trained in GMPs unless the facility also produces products for other markets. While the latter is often true for active ingredients used in over the counter medications, e.g. Isopropyl Alcohol USP and Calcium Carbonate USP, ordinarily API facilities are dedicated to GMP manufacturing. However, manufacturers of excipients generally manufacture not only other chemicals for other markets but also produce the excipient in grades suitable for other applications. Since the site often produces a small percentage of material under GMPs, the extent of employee training at such sites need not be as broad as at their pharmaceutical customer.

It is important to first identify the function at the excipient manufacturer whose personnel require training in GMP. The training of all site personnel is an unnecessary burden for excipient manufacturers who produce diverse chemicals in large volume relative to the comparatively small quantity of excipient. Thus the first step is to identify that operation in the manufacture of the excipient where full conformance to GMP begins; otherwise the site is expected to train all employees. However, it is not the purpose of this article to provide guidance on identifying the point where GMP begins.

Hourly employees involved in the manufacture of excipients, such as chemical operators, maintenance workers, laboratory technicians, and warehouse personnel as well as their supervisors, require GMP training as described in this article. Site management and quality professionals require a broader and more in-depth understanding of GMP as it relates to their responsibilities. This understanding is often achieved by site and Quality Unit management participation in seminars, public training courses and attendance at conferences.

Training for those hourly personnel noted above, should be relevant to their job function at the site. It is beneficial for the GMP trainer to be familiar not only with the excipient GMPs but also with site operations. The preferred instructor is an employee of the company who is knowledgeable in excipient GMPs.

Contractors who provide training add relevance to the training course by touring the facility, observing the various GMP operations, meeting with personnel, and reviewing the functionality of the excipient in drug products. The tour should emphasize:

  • Housekeeping
  • Area cleanliness
  • Recording of data
  • Storage of raw materials
  • Employee attire; especially during packaging operations
  • Working conditions, primarily temperature; especially during warm weather
  • Storage of tools, utensils, and other often used items
  • Warehouse orderliness

The consultant is provided with appropriate information so as to prepare training materials relevant to the participants. The presentation is tailored to incorporate site operations and those observed activities that deviate from the expectations of GMPs. Whenever allowed; the incorporation of illustrative photographs enhances an appreciation by the attendees for improvement opportunities.

GMPs provide control through consistency and standard practices to provide the pharmaceutical industry with excipients whose variation in composition is minimized. While excipient GMPs are organized in accordance with ISO 9001 , it is suggested that the employee GMP training program be conducted following the subparts of 21CFR Part 211. A suggested outline begins with discussion of the reason why training is being conducted and establishes GMP training as a requirement for the production of excipient grade materials. The trainer relates GMPs to ISO 9001 since many excipient manufacturers are certified to the ISO standard. The presenter then lists the excipients produced at the site and discusses the drug products in which they are used. The instructor relates those drugs to the attendees and their family members or friends as patients through the therapeutic effect stressing the importance of producing the excipients in accordance with instructions from their supervisors and the GMP requirements to be discussed at the training session.

Instruction then proceeds through the subparts of 21CFR Part 211 personalizing each section for the attendees as noted:

Subpart A: Note to the participants that this section is a list of definitions

Subpart B: The GMPs begin with this section, Organization and Personnel, reflecting the importance placed on employees in assuring the quality of pharmaceuticals and their ingredients and for conformance to GMP requirements. The employees are made aware of their obligation to notify their supervisor of any health-related matter that can impact the safety of the excipient. Also they are informed that GMP training is ongoing and is repeated at an established frequency.

Subpart C: Review the observations concerning buildings and facilities and discuss the impact of adverse conditions on the quality of the excipient and to the safety of the drugs that contain the excipient. Emphasis is placed on the risk of excipient contamination where the material is exposed. Of particular concern is the risk presented from insects and poor housekeeping demonstrating how the participants can affect these conditions. Instruction can challenge the attendees to discuss measures that are taken or improvements that might be made to prevent contamination of the excipient.

Subpart D: Attendees should be reminded to operate the equipment in accordance with instructions and to notify their supervisor of any failure to do so. This allows the Quality Unit to investigate the impact on excipient quality and perhaps offer the affected lot of material to another market. It is also important to motivate the attendees to maintain the cleanliness of the equipment to the extent they are able and to report issues to their supervisor.

Subpart E: This section on components, closures, and containers provides an opportunity to review the importance of keeping packaging materials free of airborne contaminants through the filling and closure of the container. Emphasis is made on the importance of properly applying the tamperevident seal to establish to the customer that the excipient container has not been opened prior to receipt by the user.

Subpart F: This section on production and process controls is an opportunity to reinforce the importance of following written instructions and to report any deviations.

Subpart G: Attendees generally are only involved in the labeling of the excipient container but their role in the prevention of mix-ups should be reviewed.

Subpart H: Holding and distribution typically only applies to warehouse personnel. However, they are critical to assuring the proper excipient grade and lot are applied to the order and so the need for attention to detail is emphasized. A dialogue can be started by asking the attendees to name precautions taken to assure order fulfillment is correct.

Subpart I: Laboratory controls apply to personnel who perform evaluation of samples. Again the emphasis is on their attention to detail as well as thorough recording of experimental details and observations. They should be instructed on the importance of retaining all raw data as part of the test record, including any measurements or observations recorded on scraps of paper. Personnel should also be requested to promptly report any instrument whose calibration due date has passed.

Subpart J: Attendees are instructed to complete records and reports in conformance with good documentation practices. They are instructed to enter all information contemporaneously. Employees are shown the proper manner to correct an error on a record and informed of the importance for completely annotating all information requested on forms. Finally employees are requested to make all entries legible and to sign and date records as instructed.

Subpart K: The final subpart, which deals with returned and salvaged products, is an opportunity to inform the attendees of the importance management places in assuring the safety of excipients in the marketplace. Thus the instructor can relate this objective to the company policy of either not salvaging returned excipient for use as an excipient grade material or of the measures taken to assure returned excipient is safe to offer for sale to pharmaceutical customers.

Oftentimes the author is asked how long this type of training session should be and with what frequency should it be conducted. Ideally the answers are derived from an evaluation of the conformance of site activities to excipient GMP expectations. Personal experience has shown that initial GMP training often requires 2 hours or so for hourly employees. Since their supervisors require more in-depth understanding and broader knowledge of the GMPs, more extensive training should be planned. The frequency and content of refresher training can be based upon a review of audit findings; both internal and external (i.e., customer or regulatory).

GMP training is delivered by qualified individuals; a combination of experience in training and training design as well as knowledge in the subject matter. Subject matter expertise is gained from attendance at a public course or work experience as demonstrated by their participation in the development and conformance of a GMP compliant quality system. This information is retained as it is subject to inspection by regulatory authorities.

The content of GMP training must be documented. This can be accomplished through retention of a copy of all training materials; often a print out of PowerPoint slides. Training materials should be reviewed for both accuracy of content and conformance to regulatory expectations. Attendance must also be documented through a signed and dated attendance sheet that clearly lists the names of the attendees as well as of the instructor.

The authors’ preference is for classroom GMP training. As noted here, personalization of GMP training supports the motivation of employees to conduct their tasks in accordance with instructions. Another benefit to the classroom method is that the trainer can convey a deeper understanding of GMPs and discussion of the employee’s role in the operation. The preferred alternative is to record the classroom training for future use while periodically verifying the continued relevance of the content. Other training techniques, i.e., generic computer based GMP training, are more cost effective unless their content is customized for the excipient operation. Such training is better suited to achieve the requirement for ongoing GMP training.

It is important to measure the effectiveness of GMP training, regardless of the method of its presentation. Students are often given a written examination to confirm comprehension. The preference of the author is to rely on performance improvements to demonstrate the effectiveness of training. Effectiveness can be verified by establishing a baseline measurement for select aspects of GMP conformance prior to training and reviewing performance subsequent to training. In practice, this is accomplished by making comparisons of areas needing improvement such as housekeeping, recordkeeping, equipment cleanliness, and deviations to demonstrate improvement.

Much has been written in the literature about conforming to Good Manufacturing Practices, but training has received scant attention. It is the goal of this article to begin a dialogue on this subject as applied to the manufacture of excipients.

Irwin Silverstein is a consultant specializing in quality assurance and regulatory compliance for pharmaceutical excipient ingredients. He also has experience in quality assurance for API, medical device and drug products.

He was formerly the Corporate Director of Quality Assurance for International Specialty Products (ISP) where he spent 17 of his 22 years leading the Quality Unit responsible for excipients, API, and medical devices. He has worked since 1991 with the International Pharmaceutical Excipients Council (IPEC) developing guidance documents for excipient GMP compliance. In addition to working as a consultant to the industry, he is the VP and Chief Operating Officer of International Pharmaceutical Excipients Auditing Inc (IPEA) where he was instrumental in developing the ANSI accredited IPEA Excipient GMP Conformance Certification program.

He began consulting as an expert consultant hired by pharmaceutical firms under FDA Consent Decree. Recent consulting includes pharmaceutical firms where he assesses conformance to site requirements and GMP gap assessments of excipient manufacturers. As an experienced GMP auditor, with American Society for Quality (ASQ) Certified Quality Auditor (CQA) status as well as ISO 9000 Certified Lead Auditor training, he has developed IPEA auditor training programs for hourly and supervisory personnel.  

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